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While Parkinsons disease remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that the disease commonly consists of multiple pathologies, but it is unclear where these co-pathologies occur early in disease and whether they are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits. Motor deficits were determined on a modified and validated Unified Parkinsons Disease Rating Scale III but were insufficient in degree to diagnose Parkinsons disease. However, in our past studies, cases in this cohort had a selection bias, as both a clinical syndrome in between no motor deficits and Parkinsons disease, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in the current study, we only based inclusion on the presence of a clinical phenotype with mild motor impairment insufficient to diagnose Parkinsons disease. Then, we divided this group further based upon whether or not subjects had a synucleinopathy in the nigrostriatal system. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation and loss of the tyrosine hydroxylase-phenotype in the substantia nigra and putamen occur equally in mild motor deficit groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8 positive phosphorylated tau, a pathology not seen in the nigrostriatal system of age-matched controls. These findings were confirmed with early (tau Ser208 phosphorylation) and late (tau Ser396/Ser404 phosphorylation) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and can be tau mediated.

A hallmark of Parkinsons disease is the specific degeneration of dopaminergic neurons in the substantia nigra pars compacta. Interestingly, not all of these neurons are affected to the same extent. Studies revealed that neurons located more ventrally within the substantia nigra pars compacta have a higher prevalence to degenerate than those located in the dorsal tier. The underlying reasons for this selective neuronal vulnerability are still unknown. The aim of the present study was to gain a better understanding of molecular differences between these two neuronal subpopulations that may explain the selective neuronal vulnerability within the human substantia nigra. For this purpose, the neurons from the ventral as well as dorsal tier of the substantia nigra were specifically isolated out of neuropathologically unremarkable human substantia nigra sections with laser microdissection. Following, their proteome was analyzed by data independent acquisition mass spectrometry. The samples were analysed donor-specifically and not pooled for this purpose. A total of 5,391 proteins were identified in the substantia nigra. Of these, 2,453 proteins could be quantified in 100% of the dorsal tier samples. 1,629 could be quantified in 100% of the ventral tier samples. Nine proteins were differentially regulated with a log2 value ≥0.5 and a Qvalue ≤0.05. Of these 7 were higher abundant in the dorsal tier and 2 higher in the ventral tier. These proteins are associated with the cytoskeleton, neuronal plasticity, or calcium homeostasis. With these findings a deeper understanding can be gained of the selective neuronal vulnerability within the substantia nigra and of protective mechanisms against neurodegeneration in specific neuronal subpopulations.

BackgroundLewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer's pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer's pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss.MethodsData were obtained from the National Alzheimer's Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss' association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer's pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models.ResultsCompared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss.ConclusionsNigral neuron loss' association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD.

Clock genes, which are essential for suprachiasmatic nucleus (SCN) function, also play critical roles in other brain regions, and their expression have been the subject of various studies. An increasingly deeper understanding of the expression of these genes in different species contributes to our knowledge of their functions and the factors influencing their expression. Considering that most studies have been conducted in nocturnal rodents, in this study we investigated the presence of Per1, Per2 and Cry1 in neurons of the substantia nigra (SN) and subthalamic nucleus (STN) in a diurnal primate. The immunoreactivity of Per1, Per2, and Cry1 was analyzed using immunohistochemistry, revealing significant Per1-IR, Per2-IR, and Cry1-IR in the SN. While Per1-IR and Per2-IR were also observed in the STN, no Cry1-IR staining was detected in the STN. These results confirm the presence of proteins that regulate circadian rhythms in areas associated with motor behavior. [ABSTRACT FROM AUTHOR]

Background and purpose Methods Results Conclusion Neurodegeneration is uneven in Parkinson's disease (PD). This study aimed to investigate spatiotemporal neurodegeneration in functional subregions of the substantia nigra (SN) and their connected cortex and subcortex in people with PD.A total of 120 patients with early‐stage PD, 45 patients with advanced PD, and 120 healthy controls (HCs) were enrolled. The SN, cortex, and subcortex were divided into sensorimotor, associative, and limbic regions, respectively. Iron deposition in the SN was assessed by quantitative susceptibility mapping (QSM). Cortex and subcortex volumes were calculated based on T1‐weighted imaging. Region of interest (ROI) analysis and voxel‐based analysis (VBA) were performed to explore spatiotemporal neurodegeneration in patients with PD. p values were corrected for false discovery rate.In the ROI analysis, the QSM values for the limbic (p = 0.018) and sensorimotor SN subregions (p = 0.018) were higher in PD patients than in HCs, but were not higher in the associative SN subregion (p = 0.295). In VBA, all SN functional subregions had clusters with higher QSM values in PD patients than in HCs (p < 0.001). The limbic SN subregion was the only one in which iron deposition increased from early‐stage to advanced PD (p = 0.023). The QSM values of VBA_limbic, sensorimotor, and associative SN had subregion‐specific correlations with disease severity (p = 0.001 for the limbic and sensorimotor subregions, p = 0.003 for the associative subregion), motor symptoms (p = 0.057 for the limbic and sensorimotor subregion), and depression scores (p = 0.036 for the limbic subregion).Iron deposition in SN functional subregions and atrophy of cortical and subcortical structures connected with the SN showed spatiotemporal selectivity. These findings reveal the potential pathogenesis of clinical heterogeneity in PD. [ABSTRACT FROM AUTHOR]

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct D1 and indirect D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These striosomal D1 (S-D1) and D2 (S-D2) pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement with net effects opposite to those exerted by the canonical pathways: S-D1 is net inhibitory and S-D2 is net excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs. • Direct S-D1 and indirect S-D2 striosomal pathways target SNpc dopamine cells • The S-D2 indirect pathway targets a distinct central zone of the GPe • Stimulation of S-D2 increases, of S-D1 decreases, striatal dopamine and movement • S-D1-S-D2 and canonical D1-D2 pathways have opposite effects on voluntary movement Lazaridis et al. delineate a previously unrecognized pair of striosomal direct D1 and indirect D2 circuits that target substantia nigra dopamine-containing neurons, controllers of mood, action, and reinforcement learning. These striosomal circuits have effects opposing those of the canonical D1-direct/D2-indirect pathways, likely modulating them. [ABSTRACT FROM AUTHOR]

[Display omitted] • MPTP is unable to induce anxiety-like behaviors and motor deficit in LXRα-/- mice. • Knockout of LXRα leads to dopaminergic neurons loss in substantia nigra. • LXRα ablation prevents MPTP-induced augmentation of glial cells reaction. • LXRα ablation alters pro-inflammatory cytokines releases. Parkinson's disease (PD) is the second most common neurodegenerative disorder whose etiology remains unknown. The immune system has been implicated in hallmarks of PD including aggregation of α-synuclein and death of dopaminergic neurons in the substantia nigra. As a core regulator of immune response and inflammation, liver X receptors (LXRs) have been shown to have protective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. With two isoforms of LXRs (LXRα and LXRβ) expressed in the brain, their roles and distributions in this tissue remain largely unexplored. Here, we used MPTP to mimic symptoms and biomedical changes seen in PD in LXRα-/- and wild-type mice to investigate the role of LXRα in the etiology and progression of PD. We found that MPTP is unable to induce motor deficits, anxiety-like behavior in LXRα-/- mice, which has been seen in WT mice. Gene ontology analysis of RNA sequencing revealed that knockout of LXRα led to enrichment of the process, including immune response and inflammation in the midbrain. In addition, MPTP did not lead to dopaminergic neuron death in the striatum and substantia nigra in LXRα-/- mice, the basal GFAP protein level, and pro-inflammatory cytokines were elevated in LXRα-/- mice. Lastly, the microglia activation and astrogliosis caused by MPTP intoxication we found in WT mice were abolished in LXRα-/- mice. To sum up, we conclude that LXRα is a critical regulator in MPTP intoxication and may play a unique role in astrogliosis seen in the neuroinflammation of PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disease characterized by the gradual loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc), abnormal accumulation of α-synuclein (α-syn), and activation of microglia leading to neuroinflammation. Disturbances in circadian rhythm play a significant role in PD, with most non-motor symptoms associated with disruptions in circadian rhythm. These disturbances can be observed years before motor symptoms appear and are marked by the emergence of non-motor symptoms related to PD, such as rapid eye movement sleep behavior disorder (RBD), restless leg syndrome (RLS), excessive daytime sleepiness (EDS), depression and anxiety, changes in blood pressure, gastrointestinal dysfunction, and urinary problems. Circadian rhythm disruption precedes the onset of motor symptoms and contributes to the progression of PD. In brief, this article outlines the role of circadian rhythm disruption in triggering PD at cellular and molecular levels, as well as its clinical manifestations. It also explores how circadian rhythm research can contribute to preventing the onset and progression of PD from current and future perspectives. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second neurodegenerative disorder most prevalent in the world, characterized by the loss of dopaminergic neurons in the Substantia Nigra (SN). It is well known for its motor and non-motor symptoms including bradykinesia, resting tremor, psychiatric, cardiorespiratory, and other dysfunctions. Pathological apoptosis contributes to a wide variety of diseases including PD. Various insults and/or cellular phenotypes have been shown to trigger distinct signaling events leading to cell death in neurons affected by PD. The intrinsic or mitochondrial pathway, inflammatory or oxidative stress-induced extrinsic pathways are the main events associated with apoptosis in PD-related neuronal loss. Although SN is the main brain area studied so far, other brain nuclei are also affected by the disease leading to non-classical motor symptoms as well as non-motor symptoms. Among these, the respiratory symptoms are often overlooked, yet they can cause discomfort and may contribute to patients shortened lifespan after disease diagnosis. While animal and in vitro models are frequently used to investigate the mechanisms involved in the pathogenesis of PD in both the SN and other brain regions, these models provide only a limited understanding of the disease's actual progression. This review offers a comprehensive overview of some of the most studied forms of cell death, including recent research on potential treatment targets for these pathways. It highlights key findings and milestones in the field, shedding light on the potential role of understanding cell death in the prevention and treatment of the PD. Therefore, unraveling the connection between these pathways and the notable pathological mechanisms observed during PD progression could enhance our comprehension of the disease's origin and provide valuable insights into potential molecular targets for the developing therapeutic interventions. [ABSTRACT FROM AUTHOR]

Introduction In recent years, a growing number of clinical and biological studies have shown that patients with type 2 diabetes mellitus (T2DM) are at increased risk of developing Parkinson's disease (PD). Prolonged exposure to hyperglycemia results in abnormal glucose metabolism, which in turn causes pathological changes similar to PD, leading to selective loss of dopaminergic neurons in the compact part of the substantia nigra. Dihydromyricetin (DHM) is a naturally occurring flavonoid with various biological activities including antioxidant and hepatoprotective properties. In this study, the effect of DHM on high glucose-induced dopaminergic neuronal damage was investigated. Methods The potential modulatory effects of DHM on high glucose-induced dopaminergic neuronal damage and its mechanism were studied. Results DHM ameliorated high glucose-induced dopaminergic neuronal damage and autophagy injury. Inhibition of autophagy by 3-methyladenine abrogated the beneficial effects of DHM on high glucose-induced dopaminergic neuronal damage. In addition, DHM increased levels of p-AMP-activated protein kinase (AMPK) and phosphorylated UNC51-like kinase 1. The AMPK inhibitor compound C eliminated DHM-induced autophagy and subsequently inhibited the ameliorative effects of DHM on high glucose-induced dopaminergic neuronal damage. Discussion DHM ameliorates high glucose-induced dopaminergic neuronal damage by activating the AMPK-autophagy pathway. [ABSTRACT FROM AUTHOR]

Multiple system atrophy is characterized pathologically by the accumulation of alpha-synuclein (aSyn) into glial cytoplasmic inclusions (GCIs). The mechanism underlying the formation of GCIs is not well understood. In this study, correlative light and electron microscopy was employed to investigate aSyn pathology in the substantia nigra and putamen of post-mortem multiple system atrophy brain donors. Three distinct types of aSyn immuno-positive inclusions were identified in oligodendrocytes, neurons and dark cells presumed to be dark microglia. Oligodendrocytes contained fibrillar GCIs that were consistently enriched with lysosomes and peroxisomes, supporting the involvement of the autophagy pathway in aSyn aggregation in multiple system atrophy. Neuronal cytoplasmic inclusions exhibited ultrastructural heterogeneity resembling both fibrillar and membranous inclusions, linking multiple systems atrophy and Parkinson's disease. The novel aSyn pathology identified in the dark cells, displayed GCI-like fibrils or non-GCI-like ultrastructures suggesting various stages of aSyn accumulation in these cells. The observation of GCI-like fibrils within dark cells suggests these cells may be an important contributor to the origin or spread of pathological aSyn in multiple system atrophy. Our results suggest a complex interplay between multiple cell types that may underlie the formation of aSyn pathology in multiple system atrophy brain and highlight the need for further investigation into cell-specific disease pathologies in multiple system atrophy. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Recent studies have highlighted the significant role of cerebrospinal fluid (CSF) in reflecting pathophysiological PD brain conditions by analyzing the components of CSF. Based on the published literature, we created a single network with altered metabolites in the CSF of patients with PD. We analyzed biological functions related to the transmembrane of mitochondria, respiration of mitochondria, neurodegeneration, and PD using a bioinformatics tool. As the proteome reflects phenotypes, we collected proteome data based on published papers, and the biological function of the single network showed similarities with that of the metabolomic network. Then, we analyzed the single network of integrated metabolome and proteome. In silico predictions based on the single network with integrated metabolomics and proteomics showed that neurodegeneration and PD were predicted to be activated. In contrast, mitochondrial transmembrane activity and respiration were predicted to be suppressed in the CSF of patients with PD. This review underscores the importance of integrated omics analyses in deciphering PD's complex biochemical networks underlying neurodegeneration. [ABSTRACT FROM AUTHOR]

Anxiety is a prominent non‐motor symptom of Parkinson's disease (PD). Changes in the B‐spectrum recordings in PD patients of the prefrontal cortex correlate with increased anxiety. Using a rodent model of PD, we reported alterations in glutamate synapses in the striatum and substantia nigra following dopamine (DA) loss. We hypothesize that DA loss will result in increased anxiety‐related behaviours and that this will be associated with alterations in glutamate synapses and transporters within the medial prefrontal cortex (mPFC). Following 4 weeks of progressive 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) administration, there was an increase in anxiety‐related behaviours and a 78% decrease in plasma corticosterone levels versus the vehicle (VEH)‐treated mice. This was associated with a 30% decrease in the density of dendritic spines in Layers Il/Ill, and a 53% decrease in the density of glutamate immuno‐gold labelling within vesicular glutamate transporter 1 (Vglut1)‐labelled nerve terminals and spines, with no change within vesicular glutamate transporter 2 (Vglut2) positive terminals/spines in the MPTP versus VEH groups. Our prior work determined that a decrease in striatal glutamate terminal density was associated with an increase in extracellular glutamate levels. There was an increase in protein expression of Vglut1 (40%), Vglut2 (37%) and glutamate aspartate transporter (GLAST) (225%), and a decrease in glutamate transporter 1 (GLT‐1) (50%) and excitatory amino acid carrier 1 (EAAC1) (51%), in the MPTP versus VEH groups within the mPFC. These data suggest that the decrease in dendritic spines within the mPFC following nigrostriatal DA loss may be due to increased extracellular glutamate levels (decrease in glutamate transporters), leading to an increase in anxiety‐related behaviours. [ABSTRACT FROM AUTHOR]

Objective: Midbrain dopamine function plays a key role in translational models of substance use disorders. Whether midbrain dopamine function is associated with substance use frequency and severity or reward function in 20–24 year-olds remains a critical gap in knowledge. The authors collected neuromelanin-sensitive magnetic resonance imaging (NM-MRI), a validated index of lifetime dopamine function in the substantia nigra/ventral tegmentum area (SN-VTA) complex, to characterize altered dopamine function. Method: Midbrain NM-MRI contrast-to-noise ratio (CNR) was acquired in 135 20–24 year-olds (105 women and 30 men). A composite measure of cumulative substance use was derived from factor analysis of lifetime alcohol intoxications, lifetime cannabis use, use of nicotine in heaviest month, number of classes of drugs used, and ever meeting DSM-5 criteria for a SUD. Trait reward function was assessed by self-report. Results: Cumulative substance use was significantly positively associated with NM-MRI CNR in a large area of the bilateral SN-VTA complex, an effect which was driven by women (who comprised most of the sample) and by voxels with greater NM-MRI CNR, including the ventral tegmentum area. NM-MRI CNR was not associated with individual differences in trait reward function. Conclusions: History of substance use is associated with greater NM signal in NM-rich areas of the midbrain, especially in women. Future longitudinal studies with repeated NM-MRI assessments, especially in younger cohorts and while including more men, are warranted to evaluate whether aberrant dopamine function predates, follows, or is modulated by substance use. [ABSTRACT FROM AUTHOR]

Background: The cannabigerol derivative VCE-003.2, which has activity at the peroxisome proliferator-activated receptor-γ has afforded neuroprotection in experimental models of Parkinson's disease (PD) based on mitochondrial dysfunction (6-hydroxydopamine-lesioned mice) and neuroinflammation (LPS-lesioned mice). Now, we aim to explore VCE-003.2 neuroprotective properties in a PD model that also involves protein dysregulation, other key event in PD pathogenesis. Methods: To this end, an adeno-associated viral vector serotype 9 coding for a mutated form of the α-synuclein gene (AAV9-SynA53T) was unilaterally delivered in the substantia nigra pars compacta (SNpc) of mice. This model leads to motor impairment and progressive loss of tyrosine hydroxylase-labelled neurons in the SNpc. Results: Oral administration of VCE-003.2 at 20 mg/kg for 14 days improved the performance of mice injected with AAV9-SynA53T in various motor tests, correlating with the preservation of tyrosine hydroxylase-labelled neurons in the SNpc. VCE-003.2 also reduced reactive microgliosis and astrogliosis in the SNpc. Furthermore, we conducted a transcriptomic analysis in the striatum of mice injected with AAV9-SynA53T and treated with either VCE-003.2 or vehicle, as well as control animals. This analysis aimed to identify gene families specifically altered by the pathology and/or VCE-003.2 treatment. Our data revealed pathology-induced changes in genes related to mitochondrial function, lysosomal cell pathways, immune responses, and lipid metabolism. In contrast, VCE-003.2 treatment predominantly affected the immune response through interferon signaling. Conclusion: Our study broadens the neuroprotective potential of VCE-003.2, previously described against mitochondrial dysfunction, oxidative stress, glial reactivity and neuroinflammation in PD. We now demonstrate its efficacy against another key pathogenic event in PD as α-synuclein dysregulation. Furthermore, our investigation sheds light on the molecular mechanisms underlying VCE-003.2 revealing its role in regulating interferon signaling. These findings, together with a favorable ADMET profile, enhance the preclinical interest of VCE-003.2 towards its future clinical development in PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a prevalent type of neurodegenerative disorder. AVE0991, a non-peptide analogue of Ang-(1–7), by which the progression of PD has been discovered to be ameliorated, but the specific mechanism whereby AVE0991 modulates the progression of PD re-mains unclear. The mice overexpressing human α-syn (A53T) were established to simulate PD pathology, and we also constructed an in vitro model of mouse dopaminergic neurons overexpressing hα-syn (A53T). The [18F] FDG-PET/CT method was employed to assess FDG uptake in human α-syn (A53T) overexpressing mice. Levels of lnc HOTAIRM1 and miR-223-3p were detected via qRT-PCR. Flow cytometry was deployed to assay cell apoptosis. Here, we found that AVE0991 improved behaviour disorders and decreased α-syn expression in the substantia nigra of mice with Parkinson's disease. AVE0991 inhibited the apoptosis of dopaminergic neurons overexpressing hα-syn (A53T) via lncRNA HOTAIRM1. MiR-223-3p binds to HOTAIRM1 as a ceRNA and directly targets α-syn. Moreover, miR-223-3p level in peripheral blood was found negatively correlated with the α-syn. Our present study shows that the angiotensin-(1–7) analogue AVE0991 targeted at the HOTAIRM1/miR-223-3p axis to degrade α-synuclein in PD mice, and showed neuroprotection in vitro. [ABSTRACT FROM AUTHOR]

Rotenone is a pesticide that causes complex I inhibition and is widely known to induce motor disability and experimental Parkinson's disease (PD) in rodents. Evidence suggests a crucial role for sirtuin/nuclear factor-kappaB/nod-like receptor family, pyrin domain-containing 3 (SIRT1/NFκB/NLRP3) signaling and inflammation in PD and rotenone neurotoxicity. Hesperetin (C16H14O6) is a citrus flavonoid with documented anti-inflammatory activity. We investigated the value of hesperetin in delaying rotenone-induced PD in mice and the possible modulation of inflammatory burden. PD was induced in mice via rotenone injections. Groups were assigned as a vehicle, PD, or PD + hesperetin (50 or 100 mg/kg) and compared for the motor function, protein level (by ELISA), and gene expression (by real-time PCR) of the target proteins, histopathology, and immunohistochemistry for tyrosine hydroxylase enzyme. Hesperetin (50 or 100 mg/kg) alleviated the motor disability and the striatal dopamine level and decreased the expression of NLRP3 and NF-κB but increased SIRT1 expression (p < 0.05). Further, it enhanced the neural viability and significantly decreased neural degeneration in the substantia nigra, hippocampus, and cerebral cortex (p < 0.05). Taken together, we propose that hesperetin mediates its neuroprotective function via alleviating modulation of the SIRT1/NFκB/NLRP3 pathway. Therefore, hesperetin might delay the PD progression. [ABSTRACT FROM AUTHOR]

• ICV injection of αSyn PFFs do not induce diffuse synucleinopathy in the brain of C57BL/6 mice. • ICV injection of αSyn PFFs do not induce olfactory dysfunction and motor incoordination in C57BL/6 mice. • ICV injection of αSyn PFFs do not affect iron deposition/redistribution in the brain of C57BL/6 mice. Alpha-synuclein (αSyn) is believed to play a central role in the pathogenesis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) total αSyn were significantly lower in PD patients, whereas the aggregates were higher, and this phenomenon was further exacerbated with longer disease duration. However, whether CSF αSyn can be the cause and/or a consequence in PD is not fully elucidated. We administered 2 ng or 200 ng αSyn preformed fibrils (PFFs) by intracerebroventricular injection for consecutive 7 days in C57BL/6 mice. The olfactory function was assessed by the olfactory discrimination test and buried food-seeking test. The locomotor function was assessed by the rotarod test, pole test, open field test and CatWalk gait analysis. Phosphorylated αSyn at serine 129 was detected by the immunohistochemistry staining. Iron levels was determined by Perl's-diaminobenzidine iron staining and synchrotron-based X-ray fluorescence. The mice did not exhibit any diffuse synucleinopathy in the brain for up to 30 weeks, although αSyn PFFs induced aggregation in SH-SY5Y cells and in the substantia nigra and striatum of mice with stereotactic injection. No impairment of motor behaviors or olfactory functions were observed, although there was a temporary motor enhancement at 1 week. We then demonstrated iron levels were comparable in certain brain regions, suggesting there was no iron deposition/redistribution occurred. The intraventricular injection of αSyn PFFs does not induce synucleinopathy or behavioral symptoms. These findings have implications that CSF αSyn aggregates may not necessarily contribute to the onset or progression in PD. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain and the formation of intracellular protein aggregates known as Lewy bodies, of which a major component is the protein α-synuclein. Several studies have suggested that mitochondria play a central role in the pathogenesis of PD, encompassing both familial and sporadic forms of the disease. Mitochondrial dysfunction is attributed to bioenergetic impairment, increased oxidative stress, damage to mitochondrial DNA, and alteration in mitochondrial morphology. These alterations may contribute to improper functioning of the central nervous system and ultimately lead to neurodegeneration. The perturbation of mitochondrial function makes it a potential target, worthy of exploration for neuroprotective therapies and to improve mitochondrial health in PD. Thus, in the current review, we provide an update on mitochondria-based therapeutic approaches toward α-synucleinopathies in PD. [ABSTRACT FROM AUTHOR]

Purpose: Parkinson disease (PD) is a common progressive neurodegenerative disorder in our ageing society. Early-stage PD biomarkers are desired for timely clinical intervention and understanding of pathophysiology. Since one of the characteristics of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, we propose a feature extraction method for analysing the differences in the substantia nigra between PD and non-PD patients. Method: We propose a feature-extraction method for volumetric images based on a rank-1 tensor decomposition. Furthermore, we apply a feature selection method that excludes common features between PD and non-PD. We collect neuromelanin images of 263 patients: 124 PD and 139 non-PD patients and divide them into training and testing datasets for experiments. We then experimentally evaluate the classification accuracy of the substantia nigra between PD and non-PD patients using the proposed feature extraction method and linear discriminant analysis. Results: The proposed method achieves a sensitivity of 0.72 and a specificity of 0.64 for our testing dataset of 66 non-PD and 42 PD patients. Furthermore, we visualise the important patterns in the substantia nigra by a linear combination of rank-1 tensors with selected features. The visualised patterns include the ventrolateral tier, where the severe loss of neurons can be observed in PD. Conclusions: We develop a new feature-extraction method for the analysis of the substantia nigra towards PD diagnosis. In the experiments, even though the classification accuracy with the proposed feature extraction method and linear discriminant analysis is lower than that of expert physicians, the results suggest the potential of tensorial feature extraction. [ABSTRACT FROM AUTHOR]

Introduction and purpose: Parkinson's disease (PD) is the second most common neurodegenerative disease, mainly characterized by motor impairment with symptoms including rigidity, bradykinesia, rest tremor, and imbalance. It develops upon degeneration of dopaminergic neurons in the substantia nigra which is associated with the neuroinflammatory process initiated by alpha-synuclein deposits. Although, levodopa replacement therapy is the gold-standard treatment, the majority of the treated patients develop dyskinesia as a side effect, resulting from altered function of dopamine receptors. It is thought that the abnormal pulsate release of dopamine can be prevented by antagonism of adenosine 2A receptors (A2ARs). Aim of the study: This review aims to outline the implications of A2AR antagonism on basal ganglia, and thus evaluate the suggested benefits of coffee consumption in PD. Material and method: The involvement of A2ARs in the pathology and treatment of PD has been analyzed based on the findings of many published studies examining the effects of A2AR modulation. Results: Blockage of A2ARs enhances the action of dopamine via D2 receptors on striatopallidal neurons, decreasing their hyperactivity, and exerts a neuroprotective effect, suppressing the neuroinflammation. Conclusions: Istradefylline, being the only approved A2AR antagonist, was able to reduce the total cumulative dose of levodopa, improve motor control, alleviate postural abnormalities, and provide a reduction in daily 'off' time experienced by patients. Recent findings suggest the effects of drinking one cup of coffee are comparable with ones obtained by the newly introduced medication, presumably via a shared action mechanism by A2AR inhibition. [ABSTRACT FROM AUTHOR]

Clinical diagnosis of progressive supranuclear palsy (PSP) is difficult due to various phenotypes. Neuropathologically, PSP is defined by neuronal loss in the basal ganglia and brainstem with widespread occurrence of neurofibrillary tangles (NFTs) and accumulation of phosphorylated tau protein in neurons and glial cells in the brain. We previously identified the point mutation p.Pro3866Ala in the Bassoon (BSN) gene in a Japanese family with PSP‐like syndrome. We newly detected BSN mutations in two autopsied PSP cases carrying p.Thr2542Met and p.Glu2759Gly, respectively. The case with p.Thr2542Met mutation showed neurological symptoms including behavioral abnormalities, cognitive dysfunction, and parkinsonism. Brain magnetic resonance imaging (MRI) showed atrophy of the midbrain tegmentum and hippocampus. Pathologically, moderate to severe loss of neurons with gliosis was also found in the substantia nigra, and there was an almost complete loss of neurons with gliosis in the transitional zone of the cornu ammonis (CA) 1 region to the subiculum. NFTs were observed in the globus pallidus, subthalamic nucleus, substantia nigra, and CA1. 4R tau‐dominant tauopathy was detected. The case with p.Glu2759Gly mutation showed neurological symptoms, including right‐dominant motor impairment, right limping gait, postural instability, and cognitive dysfunction. Brain MRI showed mild atrophy of the midbrain tegmentum and left‐dominant parietal lobe atrophy. Pathologically, NFTs were detected in the globus pallidus, subthalamic nucleus, substantia nigra, thalamus, putamen, and brainstem tegmentum. Most neurons were immunopositive for four‐repeat tau, whereas only a few of them harbored three‐repeat tau‐positive NFTs in the hippocampus. We showed the results of a pathological study of PSP cases with BSN mutations; these were two new cases. The clinical phenotypes were similar to the first case in the point of neurological symptoms. Accumulation of four‐repeat tau was dominant. Further autopsies of BSN mutation cases and further elucidation of the molecular biological mechanism are desirable. [ABSTRACT FROM AUTHOR]

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including schizophrenia and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesized to encode learning signals needed to maximize rewarded outcomes during decision‐making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward‐related learning. Here, rats acquired a two‐choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%|20% basis (correct|incorrect responses) that assessed the flexibility of behaviour to repeated reversals of response‐outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). VTA → NAcS stimulation during other phases of the behavioural task was without significant effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no significant effect on reversal learning. These findings are consistent with the notion that increased activity in the VTA → NAcS pathway disrupts behavioural flexibility by impairing learning from negative reinforcement. [ABSTRACT FROM AUTHOR]

Despite the intensive research on gut microbiome-associated diseases over the past 20 years, pharmacological methods for effectively eliminating pathobionts remain unsatisfactory. This study investigated the therapeutic potential of bacteriophages against Enterococcus faecalis, in which bacterial tyrosine decarboxylase (TDC) converts orally administered levodopa (L-DOPA) to dopamine, in an MPTP mouse model of Parkinson's disease (PD). E. faecalis bacteriophages PBEF62, PBEF66, and PBEF67 (4 × 1010 PFU total/200 µl/day), and E. faecalis cells (2 × 109 CFU/200 µl/day) were orally administered at 2-h intervals before every MPTP (i.p.) and/or L-DOPA (p.o.) treatments for 13 days. The relative abundances of E. faecalis cells and bacteriophages in the feces peaked at 4 and 12 h after administration and gradually decreased by 12 and 48 h, respectively. While the administration of E. faecalis cells eliminated the beneficial effect of L-DOPA on MPTP-induced behavioral deficits, as assessed by cylinder and rotarod tests, the co-administration of bacteriophages with bacterial cells restored this effect. The modulating effects of L-DOPA, E. faecalis, and bacteriophages on PD behavior were closely associated with choline acetyltransferase expression levels in the striatum but not with tyrosine hydroxylase in the substantia nigra of each group. Recurrence and extinction of PD behaviors following treatment with E. faecalis and/or bacteriophages were also coincident with the dopamine levels in the blood and brain tissues of PD mice. The effectiveness of L-DOPA was restored after the three types of E. faecalis bacteriophages selectively eliminated E. faecalis cells, along with the TDC gene copies and transcripts responsible for converting L-DOPA to dopamine in the gastrointestinal tract. In conclusion, a combination of bacteriophages PBEF62, PBEF66, and PBEF67 targeting E. faecalis demonstrates potential as a valuable supplement to L-DOPA therapy for PD. [ABSTRACT FROM AUTHOR]

Background: In Parkinson's patients, intestinal dysbiosis can occur years before clinical diagnosis, implicating the gut and its microbiota in the disease. Recent evidence suggests the gut microbiota may trigger body-first Parkinson Disease (PD), yet the underlying mechanisms remain unclear. This study aims to elucidate how a dysbiotic microbiome through intestinal immune alterations triggers PD-related neurodegeneration. Methods: To determine the impact of gut dysbiosis on the development and progression of PD pathology, wild-type male C57BL/6 mice were transplanted with fecal material from PD patients and age-matched healthy donors to challenge the gut-immune-brain axis. Results: This study demonstrates that patient-derived intestinal microbiota caused midbrain tyrosine hydroxylase positive (TH +) cell loss and motor dysfunction. Ileum-associated microbiota remodeling correlates with a decrease in Th17 homeostatic cells. This event led to an increase in gut inflammation and intestinal barrier disruption. In this regard, we found a decrease in CD4 + cells and an increase in pro-inflammatory cytokines in the blood of PD transplanted mice that could contribute to an increase in the permeabilization of the blood–brain-barrier, observed by an increase in mesencephalic Ig-G-positive microvascular leaks and by an increase of mesencephalic IL-17 levels, compatible with systemic inflammation. Furthermore, alpha-synuclein aggregates can spread caudo-rostrally, causing fragmentation of neuronal mitochondria. This mitochondrial damage subsequently activates innate immune responses in neurons and triggers microglial activation. Conclusions: We propose that the dysbiotic gut microbiome (dysbiome) in PD can disrupt a healthy microbiome and Th17 homeostatic immunity in the ileum mucosa, leading to a cascade effect that propagates to the brain, ultimately contributing to PD pathophysiology. Our landmark study has successfully identified new peripheral biomarkers that could be used to develop highly effective strategies to prevent the progression of PD into the brain. [ABSTRACT FROM AUTHOR]

Treatment for Parkinson's disease (PD) has been impeded by inefficient treatment results and multiple membrane barriers during drug delivery. This study reports the design, synthesis, and application of microneedles (MNs) loaded with mitochondrion-targeted liposome encapsulated iron (Fe)-isolated single-atom nanozymes (Mito@Fe-ISAzyme, MFeI), called MFeI MNs, for in situ drug delivery into the brain parenchyma and efficient enrichment of drugs in lesion sites. In in vitro experiments, MFeI can scavenge reactive oxygen species (ROS) and protect the neurons via mitochondrial targeting, guaranteeing the subsequent treatment of PD. Using PD mouse models, we compared the intravenous injection of MFeI with the brain in situ administration of MFeI MNs (in situ MFeI MNs). Results showed that in situ MFeI MNs significantly improved the deep penetration of the drug into brain parenchyma, especially in the vital pathological sites such as the substantia nigra pars compacta and striatum. Importantly, ROS elimination and neuroinflammatory remission in the lesion site were observed, thereby efficiently alleviating the behavioral disorders and pathological symptoms of PD mice. Therefore, the MNs system for in situ single-atom nanozyme liposome delivery exhibits great potential in PD treatment. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder that progressively involves brain regions with an often-predictable pattern. Damage to the brain appears to spread and worsen with time, but the molecular mechanisms underlying the region-specific distribution of AD pathology at different stages of the disease are still under-investigated. In this study, a whole-transcriptome analysis was carried out on brain samples from the hippocampus (HI), temporal and parietal cortices (TC and PC, respectively), cingulate cortex (CG), and substantia nigra (SN) of six subjects with a definite AD diagnosis and three healthy age-matched controls in duplicate. The transcriptomic results showed a greater number of differentially expressed genes (DEGs) in the TC (1571) and CG (1210) and a smaller number of DEGs in the HI (206), PC (109), and SN (60). Furthermore, the GSEA showed a difference between the group of brain areas affected early (HI and TC) and the group of areas that were subsequently involved (PC, CG, and SN). Notably, in the HI and TC, there was a significant downregulation of shared DEGs primarily involved in synaptic transmission, while in the PC, CG, and SN, there was a significant downregulation of genes primarily involved in protein folding and trafficking. The course of AD could follow a definite time- and severity-related pattern that arises from protein misfolding, as observed in the PC, CG, and SN, and leads to synaptic impairment, as observed in the HI and TC. Therefore, a map of the molecular and biological processes involved in AD pathogenesis may be traced. This could aid in the discovery of novel biological targets in order to develop effective and well-timed therapeutic approaches. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by age-dependent neurodegeneration and the accumulation of toxic phosphorylated α-synuclein (pS129-α-syn). The mechanisms underlying these crucial pathological changes remain unclear. Mutations in parkin RBR E3 ubiquitin protein ligase (PARK2), the gene encoding parkin that is phosphorylated by PTEN-induced putative kinase 1 (PINK1) to participate in mitophagy, cause early onset PD. However, current parkin-KO mouse and pig models do not exhibit neurodegeneration. In the current study, we utilized CRISPR/Cas9 technology to establish parkin-deficient monkey models at different ages. We found that parkin deficiency leads to substantia nigra neurodegeneration in adult monkey brains and that parkin phosphorylation decreases with aging, primarily due to increased insolubility of parkin. Phosphorylated parkin is important for neuroprotection and the reduction of pS129-α-syn. Consistently, overexpression of WT parkin, but not a mutant form that cannot be phosphorylated by PINK1, reduced the accumulation of pS129-α-syn. These findings identify parkin phosphorylation as a key factor in PD pathogenesis and suggest it as a promising target for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Diagnosis of dementia with Lewy bodies (DLB) is challenging, especially in the earlier stages of the disease, owing to the clinical overlap with other neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD). We aimed to identify the transcranial sonography (TCS) parameters that can help us to detect early DLB patients. Methods: In this cross-sectional study, we prospectively recruited newly diagnosed DLB patients with less than 3 years from the onset of cognitive symptoms. For comparison purposes, we also included AD and PD patients, with a disease duration of less than 3 years, and a control group. TCS was performed to assess the substantia nigra (SN) echogenicity, the width of the third ventricle, and the frontal horns of the lateral ventricles. Subsequently, TCS images were analyzed with the medical image viewer Horos in order to quantify the intensity of the echogenicity of the SN. Univariate analysis and a logistic regression model were used to identify which variables can predict the diagnosis of DLB. Results: One hundred and seven participants were included (23 DLB, 26 AD, 27 PD and 31 controls). The median age of DLB patients was 75(72–77) years, with a disease duration of 2 years. DLB and PD patients showed higher SN hyperechogenicity rates (72.73% and 81.82%, respectively) and a greater area of the SN compared to AD patients and controls (p < 0.001). DLB and AD patients had wider ventricular systems than the other study groups. The SN hyperechogenicity predicted a diagnosis of DLB with an odds ratio of 22.67 (95%CI 3.98; 129.12, p < 0.001) when compared to AD patients. Unilateral and bilateral widened frontal horns predicted diagnosis of DLB compared to PD with an odds ratio of 9.5 (95%CI 0.97; 92.83, p = 0.053) and 5.7 (95%CI 0.97; 33.6, p = 0.054), respectively. Conclusions: Echogenicity of the SN and widening of the frontal horns of lateral ventricles can predict the diagnosis of early DLB in this cohort of newly diagnosed patients, when compared to AD and PD patients. Transcranial sonography, a non-invasive tool, could be helpful for the diagnosis of DLB at its earlier stages. [ABSTRACT FROM AUTHOR]

Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin (NM)-sensitive magnetic resonance imaging provides a marker of long-term dopamine function. We examined whether midbrain NM-sensitive magnetic resonance imaging contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia than in healthy control (HC) participants and whether this correlated with dopamine synthesis capacity. One hundred fifty-four participants (schizophrenia group: n = 74, HC group: n = 80) underwent NM-sensitive magnetic resonance imaging of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n = 38) also received [18F]-DOPA positron emission tomography to measure dopamine synthesis capacity (K i cer) in the SN-VTA and striatum. SN-VTA NM-CNR was significantly higher in patients with schizophrenia than in HC participants (effect size = 0.38, p =.019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA K i cer positively correlated with SN-VTA NM-CNR (r = 0.44, p =.005) and striatal K i cer (r = 0.71, p <.001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal K i cer (r = 0.53, p =.005) and that this relationship seemed strongest between the ventral SN-VTA and associative striatum in schizophrenia. Our results suggest that NM levels are higher in patients with schizophrenia than in HC individuals, particularly in midbrain regions that project to parts of the striatum that receive innervation from the limbic and association cortices. The direct relationship between measures of NM and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and thus as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, was classically attributed to alpha-synuclein aggregation and consequent loss of dopaminergic neurons in the substantia nigra pars compacta. Recently, emerging evidence suggested a broader spectrum of contributing factors, including exosome-mediated intercellular communication, which can potentially serve as biomarkers and therapeutic targets. However, there is a remarkable lack of comprehensive studies that connect the serum exosome microRNA (miRNA) transcriptome with demographic, clinical, and neuroimaging data in PD patients. Here, we present serum exosome miRNA transcriptome data generated from four cohort studies. Two of these studies include 96 PD patients and 80 age- and gender-matched controls, with anonymised demographic, clinical, and neuroimaging data provided for PD patients. The other two studies involve 96 PD patients who were evaluated both before and after one year of treatment with rasagiline, a widely prescribed anti-parkinsonism drug. Together, the datasets provide a valuable source for understanding pathogenesis and discovering biomarkers and therapeutic targets in PD. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegia (HSP) with thin corpus callosum can be due to a variety of genetic causes, the most common of which are biallelic variants in SPG11 (HSP11). Only six cases of neuropathologic examination of HSP11 have been reported. Here we present neuropathological findings in another case of HSP11 with novel mutation (homozygous c.6439_6442del) and clinical features of three additional cases of HSP11. These four cases of HSP11 had similar disease courses with prominent lower extremity weakness and spasticity but varied cognitive symptoms and brain magnetic resonance imaging (MRI) findings. Neuropathological examination of one case included ex vivo MRI of the cerebrum, histologic and immunohistochemical evaluation, and Western blot for SPG11. The case was notable for a small cerebrum with decreased volume of cortex, white matter, and deep gray nuclei. The corpus callosum was thin, and the substantia nigra showed marked pallor. Microscopically, the cortex had normal lamination and mild loss of neurons with mild gliosis, the corpus callosum was thin with limited gliosis, and the substantia nigra had marked decrease in neurons and pigment, with minimal gliosis. In contrast, the basal ganglia, thalamus, and spinal cord (anterior horns, corticospinal, and spinocerebellar tracts) had prominent neuron loss and gliosis. Myelin‐laden macrophages were found in multiple sites but were most common in the corpus callosum. No hyperphosphorylated tau or TDP‐43 aggregates, Lewy bodies, or amyloid β plaques were found. Compared to control, SPG11 was absent in HSP11 brain and markers of autophagy were elevated by Western blot. Comparison with prior reports of HSP with thin corpus callosum and HSP11 demonstrates a disease with a broad range of structural changes of the brain, including features of abnormal development and degeneration. [ABSTRACT FROM AUTHOR]

Background: Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson's disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. Methods: aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. Results: In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Conclusions: Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD. [ABSTRACT FROM AUTHOR]

The primary pathological hallmark of Parkinson's disease (PD) is the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta, a critical midbrain region. In vitro models based on DA neurons provide a powerful platform for investigating the cellular and molecular mechanisms of PD and testing novel therapeutic strategies. A deep understanding of DA neuron development, including the signalling pathways and transcription factors involved, is essential for advancing PD research. This article first explores the differentiation and maturation processes of DA neurons in the midbrain, detailing the relevant signalling pathways. It then compares various in vitro models, including primary cells, immortalized cell lines, and stem cell‐based models, focusing on the advantages and limitations of each. Special attention is given to the role of immortalized and stem cell models in PD research. This review aims to guide researchers in selecting the most appropriate model for their specific research goals. Ethical considerations and clinical implications of using stem cells in PD research are also discussed. [ABSTRACT FROM AUTHOR]

• PD-O-α-Syn and MSA-O-α-Syn are differentially phosphorylated at serine 129. • PD-O-α-Syn and MSA-O-α-Syn have different cytotoxicity and seeding activity. • PD-O-α-Syn and MSA-O-α-Syn cause distinct dopaminergic damage and motor disorders. Previous studies have shown that α-synuclein (α-Syn) aggregates derived from the brains of patients with Parkinson's disease (PD) and multiple system atrophy (MSA) exhibit different phosphorylation, cytotoxicity, and seeding activity. However, the mechanism underlying the differences remains poorly understood. Here, recombinant human α-Syn was incubated in the plasma of patients with PD and MSA, and the oligomers formed in the plasma (PD-O-α-Syn and MSA-O-α-Syn) were purified and analyzed for their phosphorylation, cytotoxicity and seeding activity. In vitro assays revealed that both PD-O-α-Syn and MSA-O-α-Syn were phosphorylated at serine 129. However, the phosphorylation degree of MSA-O-α-Syn was significantly higher than that of PD-O-α-Syn. In addition, MSA-O-α-Syn exhibited stronger cytotoxicity and seeding activity compared with PD-O-α-Syn. In vivo experiments showed that mice receiving intrastriatal inoculation of MSA-O-α-Syn developed more severe motor dysfunction and dopaminergic degeneration than mice receiving intrastriatal inoculation of PD-O-α-Syn. Compared with the mice inoculated with PD-O-α-Syn, the mice inoculated with MSA-O-α-Syn accumulated more phosphorylated and oligomerized α-Syn in the striatum and brain regions (substantia nigra, hippocampus and prefrontal cortex) away from the inoculated site. The results obtained suggest that α-Syn oligomers formed in PD and MSA plasma are different in phosphorylation, cytotoxicity, and seeding activity. [ABSTRACT FROM AUTHOR]

Introduction: Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease characterized by dementia, cerebellar ataxia, and painful sensory disturbances. GSS is pathologically defined by the presence of amyloid plaques comprised of prion protein predominantly localized in the cerebral cortex, cerebellar cortex, and basal ganglia, resulting from mutations in the prion protein gene. Methods: This study investigated five cases of GSS P102L (GSS caused by a leucine (L) substitution of proline (P) at position 102 of the prion protein gene) with L-dopa-resistant extrapyramidal symptoms and reduced dopamine transporter single-photon emission computed tomography (DAT-SPECT) uptake. Clinical findings of the five cases were investigated, and in one autopsy case, hematoxylin and eosin staining, dopamine transporter immunostaining, and 8G8 immunostaining in the putamen and substantia nigra were performed and compared with controls. Results: Clinical findings revealed diverse manifestations, with all cases exhibiting parkinsonism, and four patients had a vertical gaze palsy. Notably, all patients showed reduced striatal DAT-SPECT uptake, indicating neurodegeneration of the nigrostriatal system. Autopsy findings in one case confirmed prion protein plaques and dopaminergic neuron loss in the substantia nigra of a patient with GSS P102L. In addition, DAT immunostaining in the putamen was reduced compared with controls, and prion protein plaques were confirmed by 8G8 immunostaining. Conclusion: This study provides support for a correlation between abnormal prion protein deposition and nigrostriatal system degeneration in GSS P102L. Our results reveal the importance of considering GSS P102L in cases of atypical Parkinsonism and abnormal DAT-SPECT results, which would serve as a valuable indicator for subsequent prion genetic testing. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. Loss or degeneration of the dopaminergic neurons in the substantia nigra and development of Lewy bodies in dopaminergic neurons were the defining pathologic changes. MiRNAs fine-tune the protein levels by posttranscriptional gene regulation. MiR-7019-3p is encoded within the fifth intron of PD-associated protein PINK1. In present study, we firstly demonstrated miR-7019-3p expression is significantly upregulated in PD mice model and neuron cell models, miR-7019-3p mainly existed in mitochondria, miR-7019-3p could regulate the structure, and function of mitochondria in neuronal cells. We predicted and verified that mitochondriaassociated protein optic atrophy 1 and 12s rRNA, 16s rRNA, and polycistronic RNA are target genes of miR-7019-3p. Finally, we proved that SP1 protein could independently regulate the expression of miR-7019-3p at the upstream. The evidences in the study suggest the role miR-7019-3p in the regulation of mitochondrial structure and function, and this kind of regulation could be implemented or promoted through the pathway of SP1-miR-7019-3p-optic atrophy 1/12s rRNA, 16s rRNA, and polycistronic RNA. Our results have suggested a promising and potential therapeutic target for reversing mitochondria dysregulation in neuronal cells during PD process. [ABSTRACT FROM AUTHOR]

Objective: To explore the impacts and possible mechanism of donepezil combined with Madopar on neuronal apoptosis and cognitive function in Parkinson's disease (PD) rats. Methods: The PD rats with successful modeling were grouped into model group (normal saline), Madopar group (11.0 mg/kg Madopar), donepezil group (0.6 mg/kg donepezil hydrochloride), and donepezil+ Madopar group (11.0 mg/kg Medopa+0.6 mg/kg donepezil hydrochloride), another 12 rats were taken as the sham operation group (normal saline). The motor function and cognitive function of the rats in each group were evaluated; the positive expression of tyrosine hydroxylase (TH) was detected by immunohistochemistry; Western blot was used to detect the expression levels of TH protein, apoptosis related proteins (cleaved caspase-3, Bax, Bcl-2) and PI3K/AKT pathway related proteins; TUNEL staining was used to detect the apoptosis rate; commercial kits were applied to detect the levels of oxidative stress indicators (MDA, SOD, GSH-Px) and inflammatory factors (IL-6, IL-18, TNF-α). Results: Compared with the sham operation group, the number of rotations in model group was increased, the fall latency was shortened, the spontaneous alternation behavior (SAB) correct rate was reduced, the escape latency was prolonged, and the number of crossing the original platform was reduced, the positive expression of TH in the substantia nigra, the expression levels of TH and Bcl-2 proteins, the activities of SOD and GSH-Px, p-PI3K/PI3K and p-AKT/AKT were decreased, the apoptosis rate of substantia nigra neurons, the expression levels of cleaved caspase-3 and Bax proteins, the content of MDA, the levels of IL-6, IL-18 and TNF- α were increased (P<0.05); the Madopar, donepezil and donepezil+Madopar could reduce the number of rotations, prolong the fall latency, increase the SAB correct rate, shorten the escape latency, and increase the number of crossing the original platform in PD rats, increased the positive expression of TH in the substantia nigra, the expression levels of TH and Bcl-2 proteins, the activities of SOD and GSH-Px, p-PI3K/PI3K and p-AKT/AKT, decreased the apoptosis rate of substantia nigra neurons, the expression levels of cleaved caspase-3 and Bax proteins, the content of MDA, and the levels of IL-6, IL-18 and TNF-α (P<0.05), and the effect of donepezil+Madopar group were significantly better than that of Madopar group and donepezil group (P<0.05). Conclusion: Donepezil combined with Madopar can reduce oxidative stress and inflammatory reaction in PD rats, and improve cognitive function, which may be achieved by activating PI3K/AKT pathway. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of cannabidiol (CBD) on emotional and cognitive symptoms in rats with intra-nigral 6-hydroxydopamine (6-OHDA) lesions. Methods: Adult male Wistar rats received bilateral intranigral 6-OHDA infusions and were tested in a battery of behavioural paradigms to evaluate non-motor symptoms. The brains were obtained to evaluate the effects of CBD on hippocampal neurogenesis. Results: 6-OHDA-lesioned rats exhibited memory impairments and despair-like behaviour in the novelty-suppressed feeding test and forced swim test, respectively. The animals also exhibited dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc), striatum, and ventral tegmental area and a reduction of hippocampal neurogenesis. CBD decreased dopaminergic neuronal loss in the SNpc, reduced the mortality rate and decreased neuroinflammation in 6-OHDA-lesioned rats. In parallel, CBD prevented memory impairments and attenuated despair-like behaviour that were induced by bilateral intranigral 6-OHDA lesions. Repeated treatment with CBD favoured the neuronal maturation of newborn neurons in the hippocampus in Parkinsonian rats. Conclusion: The present findings suggest a potential beneficial effect of CBD on non-motor symptoms induced by intra-nigral 6-OHDA infusion in rats. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by the accumulation of α‐synuclein (α‐syn) in the brain and progressive loss of dopaminergic neurons in the substantia nigra (SN) region of the brain. Although the role of neuroinflammation and cellular immunity in PD has been extensively studied, the involvement of humoral immunity mediated by antibodies and B cells has received less attention. This article provides a comprehensive review of the current understanding of humoral immunity in PD. Here, we discuss alterations in B cells in PD, including changes in their number and phenotype. Evidence mostly indicates a decrease in the quantity of B cells in PD, accompanied by a shift in the population from naïve to memory cells. Furthermore, the existence of autoantibodies that target several antigens in PD has been investigated (i.e., anti‐α‐syn autoantibodies, anti‐glial‐derived antigen antibodies, anti‐Tau antibodies, antineuromelanin antibodies, and antibodies against the renin‐angiotensin system). Several autoantibodies are generated in PD, which may either provide protection or have harmful effects on disease progression. Furthermore, we have reviewed studies focusing on the utilization of antibodies as a potential treatment for PD, both in animal and clinical trials. This review sheds light on the intricate interplay between antibodies and the pathological processes in PD, including complement system activation. Significance statement: Considering the well‐established involvement of the humoral immune system in the pathophysiology of Parkinson's disease, it is important to explore alterations in both the quantity and characteristics of B lymphocytes as the main humoral immune system cells in individuals with PD. Generally, B lymphocytes in this condition exhibit a decline in numbers and a tendency to adopt memory phenotype. Furthermore, the investigation of antibodies produced against various antigens, possessing either protective or detrimental effects may aid in enhancing our comprehension of the pathophysiological path of the disease. [ABSTRACT FROM AUTHOR]

In the last few years, a plethora of biomarkers have been proposed for the differentiation of Parkinson's disease (PD) from its mimics. Most of them consist of complex measures, often based on expensive technology, not easily employed outside research centers. MRI measures have been widely used to differentiate between PD and other parkinsonism. However, these measurements were often performed manually on small brain areas in small patient cohorts with intra- and inter-rater variability. The aim of the current review is to provide a comprehensive and updated overview of the literature on biomarkers commonly used to differentiate PD from its mimics (including parkinsonism and tremor syndromes), focusing on parameters derived by simple qualitative or quantitative measurements that can be used in routine practice. Several electrophysiological, sonographic and MRI biomarkers have shown promising results, including the blink-reflex recovery cycle, tremor analysis, sonographic or MRI assessment of substantia nigra, and several qualitative MRI signs or simple linear measures to be directly performed on MR images. The most significant issue is that most studies have been conducted on small patient cohorts from a single center, with limited reproducibility of the findings. Future studies should be carried out on larger international cohorts of patients to ensure generalizability. Moreover, research on simple biomarkers should seek measurements to differentiate patients with different diseases but similar clinical phenotypes, distinguish subtypes of the same disease, assess disease progression, and correlate biomarkers with pathological data. An even more important goal would be to predict the disease in the preclinical phase. [ABSTRACT FROM AUTHOR]

Epidemiological studies report an elevated risk of Parkinson's disease (PD) in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed dipeptidyl peptidase 4 (DPP-4) inhibitors. With an objective to characterize clinically translatable doses of DPP-4 inhibitors (gliptins) in a well-characterized PD rodent model, sitagliptin, PF-00734,200 or vehicle were orally administered to rats initiated either 7-days before or 7-days after unilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) lesioning. Measures of dopaminergic cell viability, dopamine content, neuroinflammation and neurogenesis were evaluated thereafter in ipsi- and contralateral brain. Plasma and brain incretin and DPP-4 activity levels were quantified. Furthermore, brain incretin receptor levels were age-dependently evaluated in rodents, in 6-OHDA challenged animals and human subjects with/without PD. Cellular studies evaluated neurotrophic/neuroprotective actions of combined incretin administration. Pre-treatment with oral sitagliptin or PF-00734,200 reduced methamphetamine (meth)-induced rotation post-lesioning and dopaminergic degeneration in lesioned substantia nigra pars compacta (SNc) and striatum. Direct intracerebroventricular gliptin administration lacked neuroprotective actions, indicating that systemic incretin-mediated mechanisms underpin gliptin-induced favorable brain effects. Post-treatment with a threefold higher oral gliptin dose, likewise, mitigated meth-induced rotation, dopaminergic neurodegeneration and neuroinflammation, and augmented neurogenesis. These gliptin-induced actions associated with 70–80% plasma and 20–30% brain DPP-4 inhibition, and elevated plasma and brain incretin levels. Brain incretin receptor protein levels were age-dependently maintained in rodents, preserved in rats challenged with 6-OHDA, and in humans with PD. Combined GLP-1 and GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone. In conclusion, these studies support further evaluation of the repurposing of clinically approved gliptins as a treatment strategy for PD. [ABSTRACT FROM AUTHOR]

Degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain are the main pathological changes in Parkinson's disease (PD); however, the mechanism underlying the selective vulnerability of specific neuronal populations in PD remains unclear. Here, we used single-cell RNA sequencing to identify seven cell clusters, including oligodendrocytes, neurons, astrocytes, oligodendrocyte progenitor cells, microglia, synapse-rich cells (SRCs), and endothelial cells, in the substantia nigra of a rotenone-induced rat model of PD based on marker genes and functional definitions. We found that SRCs were a previously unidentified cell subtype, and the tight interactions between SRCs and other cell populations can be improved by icaritin, which is a flavonoid extracted from Epimedium sagittatum Maxim. and exerts anti-neuroinflammatory, antioxidant, and immune-improving effects in PD. We also demonstrated that icaritin bound with transcription factors of SRCs, and icaritin application modulated synaptic characterization of SRCs, neuroinflammation, oxidative stress, and survival of dopaminergic neurons, and improved abnormal energy metabolism, amino acid metabolism, and phospholipase D metabolism of astrocytes in the substantia nigra of rats with PD. Moreover, icaritin supplementation also promotes the recovery of the physiological homeostasis of the other cell clusters to delay the pathogenesis of PD. These data uncovered previously unknown cellular diversity in a rat model of Parkinson's disease and provide insights into the promising therapeutic potential of icaritin in PD. [ABSTRACT FROM AUTHOR]

To effectively solve the problem of a small proportion of substantia nigra and midbrain regions in Magnetic Resolution Imaging (MRI) images of Parkinson's disease (PD) patients, unclear boundaries with surrounding tissues, and difficulty in accurately delineating boundaries, an improved U2-Net algorithm for Parkinson's substantia nigra midbrain image segmentation was proposed. This algorithm first improves the Residual U-blocks (RSU) and RSU-4F modules using the Shuffle Attention (SA) module, enhancing the network's attention to Parkinson's substantia nigra and midbrain blurry regions in the encoding and decoding layers. Next, replace some ordinary convolutions in RSU-4F with DynamicConv (DyConv), capture local features through dynamic convolution kernels, and improve the segmentation performance of Parkinson's images. The experimental data used clinical data, and the improved algorithm achieved Dice, Precision, Recall, and mIou of 80.27%, 89.99%, 88.88%, and 82.38% in substantia nigra segmentation, respectively. The experimental results show that this algorithm can achieve more precise segmentation of Parkinson's images. [ABSTRACT FROM AUTHOR]

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) Asyn in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies. [ABSTRACT FROM AUTHOR]

The most pronounced neuropathological feature of Parkinson's disease (PD) is the loss of dopamine (DA) neurons in the substantia nigra compacta (SNc), which depletes striatal DA. Hypothalamic oxytocin is found to be reduced in PD patients and closely interacts with the DA system, but the role of oxytocin in PD remains unclear. Here, the disturbances of endogenous oxytocin level and the substantia nigra (SN) oxytocin receptor expression in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced PD mouse model is observed, correlated with the striatal tyrosine hydroxylase (TH) expression reduction. Killing/silencing hypothalamic oxytocin neurons aggravates the vulnerability of nigrostriatal DA signal to MPTP, whereas elevating oxytocin level by intranasal delivery or microinjecting into the SN promotes the resistance. In addition, knocking out SN oxytocin receptors induces the time‐dependent reductions of SNc DA neurons, striatal TH expression, and striatal DA level by increasing neuronal excitotoxicity. These results further uncover that oxytocin dampens the excitatory synaptic inputs onto DA neurons via activating oxytocin receptor‐expressed SN GABA neurons, which target GABA(B) receptors expressed in SNc DA neuron‐projecting glutamatergic axons, to reduce excitotoxicity. Thus, besides the well‐known prosocial effect, oxytocin acts as a key endogenous factor in protecting the nigrostriatal DA system. [ABSTRACT FROM AUTHOR]

Numerous challenges hinder the development of neuroprotective treatments for Parkinson's disease, with a regularly identified issue being the lack of clinically relevant animal models. Viral vector overexpression of α‐synuclein is widely considered the most relevant model; however, this has been limited by high variability and inconsistency. One potential method of optimisation is pairing it with a secondary insult such as FN075, a synthetic molecule demonstrated to accelerate α‐synucleinopathy. Thus, the aim of this study was to investigate if sequential infusion of adeno‐associated virus (AAV)‐α‐synuclein and FN075 into the rat brain can replicate α‐synucleinopathy, nigrostriatal pathology and motor dysfunction associated with Parkinson's disease. Rats received a unilateral injection of AAV‐α‐synuclein (or AAV‐green fluorescent protein) into two sites in the substantia nigra, followed 4 weeks later by unilateral injection of FN075 (or vehicle) into the striatum. Animals underwent behavioural testing every 4 weeks until sacrifice at 20 weeks, followed by immunohistochemistry assessment post‐mortem. As anticipated, AAV‐α‐synuclein led to extensive overexpression of human α‐synuclein throughout the nigrostriatal pathway, as well as elevated levels of phosphorylated and aggregated forms of the protein. However, the sequential administration of FN075 into the striatum did not exacerbate any of the α‐synuclein pathology. Furthermore, despite the extensive α‐synuclein pathology, neither administration of AAV‐α‐synuclein nor FN075, alone or in combination, was sufficient to induce dopaminergic degeneration or motor deficits. In conclusion, this approach did not replicate the key characteristics of Parkinson's disease, and further studies are required to create more representational models for testing of novel compounds and treatments for Parkinson's disease. [ABSTRACT FROM AUTHOR]

The use of phosphodiesterase inhibitors in the treatment of Parkinson's disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 mg/kg, and L-DOPA (12.5 mg/kg), alone or in combination, on asymmetric behavior and dopamine (DA) and serotonin metabolism in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Acute administration of sildenafil at both tested doses jointly with L-DOPA significantly increased the number of contralateral rotations during a 2 h measurement compared to L-DOPA alone. The effect of a lower dose of sildenafil combined with L-DOPA was much greater in the second hour of measurement. However, the acute combined administration of a higher dose of sildenafil with L-DOPA resulted in an immediate and much stronger increase in the number of contralateral rotations compared to L-DOPA alone, already visible in the first hour of measurement. Interestingly, the chronic combined administration of 2 mg/kg of sildenafil and L-DOPA significantly reduced the number of contralateral rotations, especially during the first hour of measurement, compared to the long-term treatment with L-DOPA alone. Such an effect was not observed after the long-term combined treatment of a higher dose of sildenafil and L-DOPA compared to L-DOPA alone. The concentration of DA in the ipsilateral striatum and substantia nigra after the last combined chronic dose of sildenafil (2 or 6 mg/kg) and L-DOPA (12.5 mg/kg) was significantly higher than after L-DOPA alone. In spite of much stronger increases in the DA concentration in the ipsilateral striatum and substantia nigra, the number of contralateral rotations was reduced in the group of rats treated with the combination of 2 mg/kg sildenafil and L-DOPA compared to the group receiving L-DOPA alone. Moreover, the combined treatment with a low dose of sildenafil and L-DOPA had an opposite effect on DA catabolism, as assessed by DOPAC/DA and HVA/DA indexes, and these indexes were reduced in the ipsilateral striatum but increased in the contralateral striatum and substantia nigra compared to the treatment with L-DOPA alone. The results of the present study show that the addition of a low dose of a PDE5 inhibitor to the standard L-DOPA therapy differently modulates rotational behavior, the tissue DA concentration and its catabolism in the striatum and substantia nigra. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a globally prevalent neurodegenerative disorder, primarily characterized by muscle rigidity, resting tremor, and bradykinesia. The incidence of PD is rapidly escalating worldwide. Numerous studies have been conducted on the application of magnetic resonance imaging (MRI) in investigating the substantia nigra (SN) in PD patients. However, to date, no bibliometric analysis has been performed on this specific research area. Therefore, this study aimed to provide a comprehensive analysis of the current status in MRI research on the SN in PD patients. Materials and methods: MRI study records related to the SN in PD patients from 2001 to 2024 were searched by using the Web of Science Core Collection (WOSCC) database and then the CiteSpace and VOSviewer were used to conduct bibliometric analysis. Results: Our analysis found that the number of published articles related studies on MRI of the SN in PD showed an overall upward trend over the past decade, in which Lehericy, Stephane, Du, Guangwei, and Huang, Xuemei are the top three authors with the most articles. Additionally, United States, China and Germany are the main contributors to MRI studies of SN in PD. And Shanghai Jiao Tong University, University of Florida and Seoul National University are the leading institutions in the field. Finally, the keyword analysis showed that the hotspots and trends of research in this field are mainly concentrated in quantitative susceptibility mapping, neuroimaging, and neuromelanin-sensitive MRI. Conclusion: These analysis identified the most influential authors, institutions, countries and research hotspots in the field of SN-MRI research in PD, which has reference significance for the research interest in this field and provides a new idea for PD prevention. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur- binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila ortholog of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target. [ABSTRACT FROM AUTHOR]