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Huntingtons Disease (HD) is a neurodegenerative disorder caused by an autosomal-dominant mutation in the huntingtin gene, which manifests with a triad of motor, cognitive and psychiatric declines. Individuals with HD often present with disturbed sleep/wake cycles, but it is still debated whether altered circadian rhythms are intrinsic to its aetiopathology or a consequence. Conversely, it is well established that sleep/wake disturbances, perhaps acting in concert with other pathophysiological mechanisms, worsen the impact of the disease on cognitive and motor functions and are a burden to the patients and their caretakers. Currently, there is no cure to stop the progression of HD, however, preclinical research is providing cementing evidence that restoring the fluctuation of the circadian rhythms can assist in delaying the onset and slowing progression of HD. Here we highlight the application of circadian-based interventions in preclinical models and provide insights into their potential translation in clinical practice. Interventions aimed at improving sleep/wake cycles synchronization have shown to improve motor and cognitive deficits in HD models. Therefore, a strong support for their suitability to ameliorate HD symptoms in humans emerges from the literature, albeit with gaps in our knowledge on the underlying mechanisms and possible risks associated with their implementation.

Understanding the normal function of the Huntingtin (HTT) protein is of significance in the design and implementation of therapeutic strategies for Huntington's disease (HD). Expansion of the CAG repeat in the HTT gene, encoding an expanded polyglutamine (polyQ) repeat within the HTT protein, causes HD and may compromise HTT's normal activity contributing to HD pathology. Here, we investigated the previously defined role of HTT in autophagy specifically through studying HTT's association with ubiquitin. We find that HTT interacts directly with ubiquitin in vitro. Tandem affinity purification was used to identify ubiquitinated and ubiquitin-associated proteins that copurify with a HTT N-terminal fragment under basal conditions. Copurification is enhanced by HTT polyQ expansion and reduced by mimicking HTT serine 421 phosphorylation. The identified HTT-interacting proteins include RNA-binding proteins (RBPs) involved in mRNA translation, proteins enriched in stress granules, the nuclear proteome, the defective ribosomal products (DRiPs) proteome and the brain-derived autophagosomal proteome. To determine whether the proteins interacting with HTT are autophagic targets, HTT knockout (KO) cells and immunoprecipitation of lysosomes were used to investigate autophagy in the absence of HTT. HTT KO was associated with reduced abundance of mitochondrial proteins in the lysosome, indicating a potential compromise in basal mitophagy, and increased lysosomal abundance of RBPs which may result from compensatory up-regulation of starvation-induced macroautophagy. We suggest HTT is critical for appropriate basal clearance of mitochondrial proteins and RBPs, hence reduced HTT proteostatic function with mutation may contribute to the neuropathology of HD.

Huntingtons disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The repeat-expanded HTT encodes a mutated HTT (mHTT), which is known to induce DNA double-strand breaks (DSBs), activation of the cGAS-STING pathway, and apoptosis in HD. However, the mechanism by which mHTT triggers these events is unknown. Here, we show that HTT interacts with both exonuclease 1 (Exo1) and MutLα (MLH1-PMS2), a negative regulator of Exo1. While the HTT-Exo1 interaction suppresses the Exo1-catalyzed DNA end resection during DSB repair, the HTT-MutLα interaction functions to stabilize MLH1. However, mHTT displays a significantly reduced interaction with Exo1 or MutLα, thereby losing the ability to regulate Exo1. Thus, cells expressing mHTT exhibit rapid MLH1 degradation and hyperactive DNA excision, which causes severe DNA damage and cytosolic DNA accumulation. This activates the cGAS-STING pathway to mediate apoptosis. Therefore, we have identified unique functions for both HTT and mHTT in modulating DNA repair and the cGAS-STING pathway-mediated apoptosis by interacting with MLH1. Our work elucidates the mechanism by which mHTT causes HD.

Axonal degeneration is a key component of neurodegenerative diseases such as Huntington's disease (HD), Alzheimer's disease, and amyotrophic lateral sclerosis. Nicotinamide, an NAD+ precursor, has long since been implicated in axonal protection and reduction of degeneration. However, studies on nicotinamide (NAm) supplementation in humans indicate that NAm has no protective effect. Sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1) regulates several cell responses to axonal damage and has been implicated in promoting neuronal degeneration. SARM1 inhibition seems to result in protection from neuronal degeneration while hydrogen peroxide has been implicated in oxidative stress and axonal degeneration. The effects of laser-induced axonal damage in wild-type and HD dorsal root ganglion cells treated with NAm, hydrogen peroxide (H2 O2 ), and SARM1 inhibitor DSRM-3716 were investigated and the cell body width, axon width, axonal strength, and axon shrinkage post laser-induced injury were measured.

Sleep disturbances are common features of neurodegenerative disorders including Huntingtons disease (HD). Sleep and circadian disruptions are recapitulated in animal models, providing the opportunity to evaluate the effectiveness of circadian interventions as countermeasures for neurodegenerative disease. For instance, time restricted feeding (TRF) successfully improved activity rhythms, sleep behavior and motor performance in mouse models of HD. Seeking to determine if these benefits extend to physiological measures of sleep, electroencephalography (EEG) was used to measure sleep/wake states and polysomnographic patterns in male and female wild-type (WT) and bacterial artificial chromosome transgenic (BACHD) adult mice, under TRF and ad lib feeding (ALF). Our findings show that male, but not female, BACHD mice exhibited significant changes in the temporal patterning of wake and non-rapid eye movement (NREM) sleep. The TRF intervention reduced the inappropriate early morning activity by increasing NREM sleep in the male BACHD mice. In addition, the scheduled feeding reduced sleep fragmentation (# bouts) in the male BACHD mice. The phase of the rhythm in rapid-eye movement (REM) sleep was significantly altered by the scheduled feeding in a sex-dependent manner. The treatment did impact the power spectral curves during the day in male but not female mice regardless of the genotype. Sleep homeostasis, as measured by the response to six hours of gentle handling, was not altered by the diet. Thus, TRF improves the temporal patterning and fragmentation of NREM sleep without impacting sleep homeostasis. This work adds critical support to the view that sleep is a modifiable risk factor in neurodegenerative diseases.

Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.

Post-translational modifications (PTMs) of proteins play a significant role in normal protein function but can also be instrumental in disease pathogenesis. One critical yet under-studied PTM in disease is ubiquitination. Ubiquitin chain addition and substrate specificity are determined by a large spectrum of ubiquitin-ligating and -modifying enzymes, E3 ligases, whose expression levels and activities are tightly regulated in a cell-specific manner. While most ubiquitin chains can target proteins for proteasomal degradation, ubiquitination can contribute to other functions within the cell, including protein localization, protein activity, endocytosis, transcription, and autophagy. One E3 ligase, UBE3A, has garnered much attention because of its involvement in learning and memory, as well as its association with neurodevelopmental autism spectrum disorders (ASDs). However, more recent findings have suggested a potential involvement of UBE3A in neurodegenerative proteinopathies, where reduced UBE3A levels can lead to an enhanced rate of aggregate formation and cell death. Here, we review the literature on UBE3A in neurodevelopment, function, and neurodegenerative diseases and demonstrate that UBE3A could play a critical role in disease progression and cognitive function. [ABSTRACT FROM AUTHOR]

In Huntington's disease (HD), aberrant processing of huntingtin (HTT) mRNA produces HTT1a transcripts that encode the pathogenic HTT exon 1 protein. The mechanisms behind HTT1a production are not fully understood. Considering the role of m6A in RNA processing and splicing, we investigated its involvement in HTT1a generation. Here, we show that m6A methylation is increased before the cryptic poly(A) sites (IpA1 and IpA2) within the huntingtin RNA in the striatum of Hdh+/Q111 mice and human HD samples. We further assessed m6A's role in mutant Htt mRNA processing by pharmacological inhibition and knockdown of METTL3, as well as targeted demethylation of Htt intron 1 using a dCas13-ALKBH5 system in HD mouse cells. Our data reveal that Htt1a transcript levels are regulated by both METTL3 and the methylation status of Htt intron 1. They also show that m6A methylation in intron 1 depends on expanded CAG repeats. Our findings highlight a potential role for m6A in aberrant splicing of Htt mRNA. Synopsis: This study unveils that m6A RNA modification contributes to aberrant Htt splicing in Huntington's disease models, promoting the generation of the pathogenic Htt1a variant. Increased m6A methylation levels in Htt1a are detected at early stages in the striatum of Hdh+/Q111 mice. HD mice and human samples reveal m6A methylation in the same intronic DRACH motif located in intron 1 of huntingtin RNA. Pharmacological inhibition and siRNA knockdown of METTL3, as well as targeted demethylation, reduce Htt1a expression in mouse cells. Blocking CAG repeats in exon 1 of Huntingtin RNA with LNA-CTG ASOs reduces m6A RNA methylation in intron 1 in mouse cells. This study unveils that m6A RNA modification contributes to aberrant Htt splicing in Huntington's disease models, promoting the generation of the pathogenic Htt1a variant. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor dysfunction and cognitive decline. While retinal abnormalities have been documented in some HD patients and animal models, the nature of these abnormalities—specifically whether they originate in the inner or outer retina—remains unclear, particularly regarding their progression with age. This study investigates the retinal structure and function in HD transgenic mice (R6/1) compared to C57BL/6 J control mice at 2, 4, and 6 months of age, encompassing both pre-symptomatic and symptomatic stages of HD. Pathological assessments of the striatum and evaluations of motor function confirmed significant HD-related alterations in R6/1 mice at 6 months. Visual function was subsequently analyzed, accompanied by immunofluorescent staining of retinal and optic nerve tissues over time. Our findings revealed that R6/1 mice exhibited pronounced HD symptoms at 6 months, characterized by neuronal loss in the striatum and impaired locomotor abilities. Functionally, visual acuity declined at 6 months, while retinal light responses began to deteriorate by 4 months. Structurally, R6/1 mice demonstrated a global reduction in cone opsin expression as early as 2 months, with a decrease in rhodopsin levels at 4 months, alongside a thinner retinal structure compared to controls. Notably, rod bipolar cell populations were decreased at 6 months, exhibiting shorter dendritic branches and reduced synaptic connections with photoreceptors in the outer retina. Additionally, ganglion cell numbers in the inner retina decreased at 6 months, accompanied by aberrant neural fibers in the optic nerve. Microglial activation was evident at 4 months, while astrocytic activation was observed at 6 months. Aggregates of mutant huntingtin (mHTT) were first detected in the ganglion cell layer and optic nerve at 2 months, subsequently disseminating throughout all retinal layers with advancing age. These results indicate that retinal pathology in R6/1 mice manifests earlier in the outer retina than in the inner retina, which does not align with the progression of mHTT aggregation. Consequently, the R6/1 mouse retina may serve as a more effective model for elucidating the mechanisms underlying HD and evaluating potential therapeutic strategies, rather than functioning as an early diagnostic tool for the disease. [ABSTRACT FROM AUTHOR]

Background: The exact pathogenesis of Huntington's disease (HD) remains unclear. However, mitochondrial dysfunction and oxidative stress are supposed to play a significant role. The objective of this study was to examine the possible neuroprotective effect of Lisinopril (Lisino) in a 3-nitropropionic acid-produced HD in rats. Methods: Sixty-four rats were divided into four groups (16/group): Group (1): Normal control group, Group (2): Lisinopril control group, Group (3): 3-NP non-treated group, and Group (4): (3-NP + Lisinopril) group. Behavior assessments (open field test, rotarod test, grip strength test) were performed along with different histological and biochemical parameters. Results: Lisinopril upregulated the expression of the ACE2/Ang1-7/MAS receptor (MasR) axis of RAS, which triggered the PI3K/Akt pathway and prompted the CREB/BDNF neurogenesis signal. Furthermore, Lisinopril remarkably downregulated the inflammatory cytokines (NF-κB, TNF-α, IFN-γ and IL-6), decreased apoptotic markers (p53, BAX/Bcl2 ratio, Cyt-c and caspase-3) and upgraded the mitochondrial TFAM content and SDH activity along with restoration of the redox mechanism by recovering SOD, catalase, GSH and Nrf2. Conclusion: Notably, the outcomes of this study disclosed that Lisinopril could be a future neuroprotective therapeutic candidate against HD. Research highlights: Lisinopril alleviated the mitochondrial dysfunction and restored redox balance via Nrf2/TFAM signaling. Lisinopril downregulated the inflammatory cytokines (NF-κB, TNF-α, IFN-γ and IL-6). Lisinopril upregulated the expression of ACE2/Ang1-7/MAS receptor axis of RAS. Lisinopril activated PI3K/Akt/CREB pathway and evoked the neurogenesis via its downstream product BDNF. Lisinopril could be a future neuroprotective treatment against Huntington disease. [ABSTRACT FROM AUTHOR]

Background: Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease. Objective: This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes. Methods: In this cross‐sectional study, we measured skin tau levels using enzyme‐linked immunosorbent assay in 23 Huntington's disease mutations carriers and eight control subjects, examining group discrimination, correlations with genetic markers, clinical assessments, and neuroimaging data. Brain atrophy was quantified by both volumetric measurements from brain segmentation and a voxel‐based morphometry approach. Results: Our findings showed elevated skin tau levels in manifest Huntington's disease compared with premanifest and healthy controls. These levels correlated with CAG repeat length, CAG‐Age‐Product score, composite Unified Huntington's Disease Rating Scale Total Motor Score, cognitive assessments, and disease‐related cortical and subcortical volumes, all independent of age and gender. Using skin tau levels in cluster analysis along with genetic and clinical measures led to improved subject stratification, providing enhanced distinction and validity of clusters. Conclusions: This study not only confirms the feasibility of skin tau quantification in Huntington's disease but also establishes its potential as a biomarker for enhancing group classification and assessing disease severity across the Huntington's disease spectrum, opening new directions in biomarker research. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Latin America has played a crucial role in advancing our understanding of Huntington's disease (HD). However, previous global reviews include limited data from Latin America. It is possible that English‐based medical search engines may not capture all the relevant studies. Methods: We searched databases in Spanish, Portuguese, and English. The names of every country in Latin America in English‐based search engines were used to ensure we found any study that had molecular ascertainment and provided general epidemiological information or subpopulation data. Additionally, we contacted experts across the region. Results: The search strategy yielded 791 citations; 24 studies met inclusion criteria, representing 12 of 36 countries. The overall pooled prevalence was 0.64 per 100,000 (prediction interval, 0.06–7.22); for cluster regions, it was 54 per 100,000 (95% CI, 34.79–84.92); for juvenile HD, it was 8.7% (prediction interval, 5.12–14.35), and 5.9% (prediction interval, 2.72–13.42) for late‐onset HD. The prevalence was higher for Mexico, Peru, and Brazil. However, there were no significant differences between Central America and the Caribbean versus South America. Conclusion: The prevalence of HD appears to be similar across Latin America. However, we infer that our findings are underestimates, in part because of limited research and underdiagnosis of HD because of limited access to molecular testing and the availability of neurologists and movement disorders specialists. Future research should focus on identifying pathways to improve access to molecular testing and education and understanding differences among different ancestral groups in Latin America. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti‐apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a CAG tract expansion in the huntingtin gene (HTT). HD is characterized by involuntary movements, cognitive decline, and behavioral changes. Pathologically, patients with HD show selective striatal neuronal vulnerability at the early disease stage, although the mutant protein is ubiquitously expressed. Activation of the immune system and glial cell-mediated neuroinflammatory responses are early pathological features and have been found in all neurodegenerative diseases (NDDs), including HD. However, the role of inflammation in HD, as well as its therapeutic significance, has been less extensively studied compared to other NDDs. This review highlights the significantly elevated levels of inflammatory proteins and cellular markers observed in various HD animal models and HD patient tissues, emphasizing the critical roles of microglia, astrocytes, and oligodendrocytes in mediating neuroinflammation in HD. Moreover, it expands on recent discoveries related to the peripheral immune system's involvement in HD. Although current immunomodulatory treatments and inflammatory biomarkers for adjunctive diagnosis in HD are limited, targeting inflammation in combination with other therapies, along with comprehensive personalized treatment approaches, shows promising therapeutic potential. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the HTT gene, leading to the formation of a toxic variant of the huntingtin protein. It is a rare but severe hereditary disease for which no effective treatment method has been found yet. The primary therapeutic targets include the mutant protein and the mutant mRNA of HTT. Current clinical trial approaches in gene therapy involve the application of splice modulation, siRNA, or antisense oligonucleotides for RNA-targeted knockdown of HTT. However, these approaches do not take into account the diversity of HTT transcript isoforms in the normal conditions and in HD. In this review, we discuss the features of transcriptional regulation and processing that lead to the formation of various HTT mRNA variants, each of which may uniquely contribute to the progression of the disease. Furthermore, understanding the role of known transcription factors of HTT in pathology may aid in the development of potentially new therapeutic tools based on endogenous regulators. [ABSTRACT FROM AUTHOR]

Research suggests that individuals with Huntington's disease (HD) perform better than individuals with Alzheimer's disease (AD) on the California Verbal Learning Test (CVLT) Yes/No Recognition trial. However, those with HD have been shown to have deficits comparable to those with AD on the Source Recognition Discriminability (RD) index (which assesses the ability to distinguish between List A targets and List B distractors), suggesting that HD may involve selective impairment in aspects of yes/no recognition that rely on source memory. However, whether individuals with HD and AD show comparable deficits on Source RD across stages of dementia severity has not been adequately investigated. We examined performance on the CVLT-3 List A vs. List B RD index in individuals with HD or AD and mild or moderate dementia. Among individuals with mild dementia, scores were higher in the HD versus AD group, whereas among individuals with moderate dementia, scores were comparable between the HD and AD groups; this corresponded to differential performance across dementia stages among individuals with HD, but not AD. The present findings suggest that, relative to AD, HD may be associated with disproportionate decline in aspects of yes/no recognition that rely on source memory. [ABSTRACT FROM AUTHOR]

In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Huntington's Disease is a rare neurodegenerative disorder in which appropriate medication management is essential. While many medications are prescribed based on expert knowledge, overviews of actual medication use in HD are sparse.We provide a detailed overview of medication use and associated indications across HD disease stages, considering sex and regional differences.Data from the largest observational HD study, ENROLL‐HD, were used. We created HD‐related medication and indication classes to identify medication trends in manifest, premanifest and control subjects. We studied medication use in adult, childhood‐ and adolescent‐onset HD, incorporating disease stage (including phenoconverters), sex and regional differences.In 8546 manifest HD patients, 84.6% used medication (any type), with the average number of medications per user rising from 2.5 in premanifest HD to 5.2 in end stage disease. Antipsychotics (29.2%), SSRIs (27.5%) and painkillers (21.8%) were most often used. Medication use varied with disease progression. Several differences were observed between the sexes, and notably between Europe and Northern America as well. Medication use increased after phenoconversion (from 64.8% to 70.6%, P < 0.05), with the largest difference in antipsychotic use (4.4%–7.8%, P < 0.05). Medication patterns were different in childhood‐onset HD, with no use of painkillers, less use of anti‐chorea and antidepressant drugs, and more for aggression and irritability.Medication use in HD increases with disease progression, with varying types of medications prescribed based on disease stage, sex, and region of living. Recognizing these medication trends is vital for further personalized HD management. [ABSTRACT FROM AUTHOR]

Background: Therapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD. Methods: Longitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology. Results: Plasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF. Conclusions: Our data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a hereditary neurological disorder caused by mutations in HTT, leading to neuronal degeneration. Traditionally, HD is associated with the misfolding and aggregation of mutant huntingtin due to an extended polyglutamine domain encoded by an expanded CAG tract. However, recent research has also highlighted the role of global transcriptional dysregulation in HD pathology. However, understanding the intricate relationship between mRNA expression and HD at the cellular level remains challenging. Our study aimed to elucidate the underlying mechanisms of HD pathology using single-cell sequencing data. Results: We used single-cell RNA sequencing analysis to determine differential gene expression patterns between healthy and HD cells. HD cells were effectively modeled using a residual neural network (ResNet), which outperformed traditional and convolutional neural networks. Despite the efficacy of our approach, the F1 score for the test set was 96.53%. Using the SHapley Additive exPlanations (SHAP) algorithm, we identified genes influencing HD prediction and revealed their roles in HD pathobiology, such as in the regulation of cellular iron metabolism and mitochondrial function. SHAP analysis also revealed low-abundance genes that were overlooked by traditional differential expression analysis, emphasizing its effectiveness in identifying biologically relevant genes for distinguishing between healthy and HD cells. Overall, the integration of single-cell RNA sequencing data and deep learning models provides valuable insights into HD pathology. Conclusion: We developed the model capable of analyzing HD at single-cell transcriptomic level. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a devastating neurodegenerative disease that is manifested by a gradual loss of physical, cognitive, and mental abilities. As the disease advances, age has a major impact on the pathogenic signature of mutant huntingtin (mHTT) protein aggregation. This review aims to explore the intricate relationship between aging, mHTT toxicity, and cellular senescence in HD. Scientific data on the interplay between aging, mHTT, and cellular senescence in HD were collected from several academic databases, including PubMed, Google Scholar, Google, and ScienceDirect. The search terms employed were "AGING," "HUNTINGTON'S DISEASE," "MUTANT HUNTINGTIN," and "CELLULAR SENESCENCE." Additionally, to gather information on the molecular mechanisms and potential therapeutic targets, the search was extended to include relevant terms such as "DNA DAMAGE," "OXIDATIVE STRESS," and "AUTOPHAGY." According to research, aging leads to worsening HD pathophysiology through some processes. As a result of the mHTT accumulation, cellular senescence is promoted, which causes DNA damage, oxidative stress, decreased autophagy, and increased inflammatory responses. Pro‐inflammatory cytokines and other substances are released by senescent cells, which may worsen the neuronal damage and the course of the disease. It has been shown that treatments directed at these pathways reduce some of the HD symptoms and enhance longevity in experimental animals, pointing to a new possibility of treating the condition. Through their amplification of the harmful effects of mHTT, aging and cellular senescence play crucial roles in the development of HD. Comprehending these interplays creates novel opportunities for therapeutic measures targeted at alleviating cellular aging and enhancing HD patients' quality of life. [ABSTRACT FROM AUTHOR]

Despite the advances in the understanding of Huntington's disease (HD), there is a need for molecular biomarkers to categorize mutation carriers during the preclinical stage of the disease preceding functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological processes. Here, using an optimized method for plasma extracellular vesicles (EVs) purification and an exhaustive analysis pipeline of sRNA sequencing data, we show that EV‐sRNAs are downregulated early in mutation carriers and that this deregulation is associated with premanifest cognitive performance. Seven candidate sRNAs (tRF‐Glu‐CTC, tRF‐Gly‐GCC, miR‐451a, miR‐21‐5p, miR‐26a‐5p, miR‐27a‐3p and let7a‐5p) were validated in additional subjects, showing a significant diagnostic accuracy at premanifest stages. Of these, miR‐21‐5p was significantly decreased over time in a longitudinal study; and miR‐21‐5p and miR‐26a‐5p levels correlated with cognitive changes in the premanifest cohort. In summary, the present results suggest that deregulated plasma EV‐sRNAs define an early biosignature in mutation carriers with specific species highlighting the progression and cognitive changes occurring at the premanifest stage. [ABSTRACT FROM AUTHOR]

Cannabis sativa is known for producing over 120 distinct phytocannabinoids, with Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) being the most prominent, primarily in their acidic forms. Beyond Δ9-THC and CBD, a wide array of lesser-known phytocannabinoids, along with terpenes, flavonoids, and alkaloids, demonstrate diverse pharmacological activities, interacting with the endocannabinoid system (eCB) and other biological pathways. These compounds, characterized by phenolic structures and hydroxyl groups, possess lipophilic properties, allowing them to cross the blood–brain barrier (BBB) effectively. Notably, their antioxidant, anti-inflammatory, and neuro-modulatory effects position them as promising agents in treating neurodegenerative disorders. While research has extensively examined the neuropsychiatric and neuroprotective effects of Δ9-THC, other minor phytocannabinoids remain underexplored. Due to the well-established neuroprotective potential of CBD, there is growing interest in the therapeutic benefits of non-psychotropic minor phytocannabinoids (NMPs) in brain disorders. This review highlights the emerging research on these lesser-known compounds and their neuroprotective potential. It offers insights into their therapeutic applications across various major neurological conditions. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is marked by irreversible loss of neuronal function for which currently no availability for disease‐modifying treatment exists. Advances in the understanding of disease progression can aid biomarker development, which in turn can accelerate therapeutic discovery. Methods: We characterised the progression of altered dynamics of whole‐brain network states in the zQ175DN mouse model of HD using a dynamic functional connectivity (FC) approach to resting‐state fMRI and identified quasi‐periodic patterns (QPPs) of brain activity constituting the most prominent resting‐state networks. Results: The occurrence of the normative QPPs, as observed in healthy controls, was reduced in the HD model as the phenotype progressed. This uncovered progressive cessation of synchronous brain activity with phenotypic progression, which is not observed with the conventional static FC approaches. To better understand the potential underlying cause of the observed changes in these brain states, we further assessed how mutant huntingtin (mHTT) protein deposition affects astrocytes and pericytes – one of the most important effectors of neurovascular coupling, along phenotypic progression. Increased cell‐type dependent mHTT deposition was observed at the age of onset of motor anomalies, in the caudate putamen, somatosensory and motor cortex, regions that are prominently involved in HD pathology as seen in humans. Conclusion: Our findings provide meaningful insights into the development and progression of altered functional brain dynamics in this HD model and open new avenues in assessing the dynamics of whole brain states, through QPPs, in clinical HD research. Highlights: Hyperactivity in the LCN‐linked regions within short QPPs observed before motor impairment onset.DMLN QPP presents a progressive decrease in DMLN activity and occurrence along HD‐like phenotype development.Breakdown of the LCN DMLN state flux at motor onset leads to a subsequent absence of the LCN DMLN QPP at an advanced HD‐like stage. [ABSTRACT FROM AUTHOR]

Background: Clinical trial scenarios can be modeled using data from observational studies, providing critical information for design of real‐world trials. The Huntington's Disease Integrated Staging System (HD‐ISS) characterizes disease progression over an individual's lifespan and allows for flexibility in the design of trials with the goal of delaying progression. Enrichment methods can be applied to the HD‐ISS to identify subgroups requiring smaller estimated sample sizes. Objective: Investigate time to the event of functional decline (HD‐ISS Stage 3) as an endpoint for trials in HD and present sample size estimates after enrichment. Methods: We classified individuals from observational studies according to the HD‐ISS. We assessed the ability of the prognostic index normed (PIN) and its components to predict time to HD‐ISS Stage 3. For enrichment, we formed groups from deciles of the baseline PIN distribution for HD‐ISS Stage 2 participants. We selected enrichment subgroups closer to Stage 3 transition and estimated sample sizes, using delay in the transition time as the effect size. Results: In predicting time to HD‐ISS Stage 3, PIN outperforms its components. Survival curves for each PIN decile show that groups with PIN from 1.48 to 2.74 have median time to Stage 3 of approximately 2 years and these are combined to create enrichment subgroups. Sample size estimates are presented by enrichment subgroup. Conclusions: PIN is predictive of functional decline. A delay of 9 months or more in the transition to Stage 3 for an enriched sample yields feasible sample size estimates, demonstrating that this approach can aid in planning future trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)-ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell-derived neurons and patient-derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR-binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild-type and mutant HTT did not differ in their PAR binding ability, purified wild-type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a debilitating neurodegenerative disorder caused by an abnormal expansion of CAG repeats (Cytosine, Adenine, Guanine) in the huntingtin gene (HTT). This mutation leads to the production of a mutant huntingtin protein, resulting in neuronal dysfunction and cell death. Current treatments primarily focus on symptomatic relief and do not address the underlying genetic cause. This review explores spliceosome-mediated RNA trans-splicing (SMaRT) therapy as an innovative and potential approach for HD treatment. SMaRT leverages the cell's natural splicing machinery to correct mutant mRNA, thereby reducing toxic protein levels while restoring functional protein production. We compare SMaRT with other gene therapy strategies, such as antisense oligonucleotides, RNA interference, and CRISPR-based systems, highlighting SMaRT's dual-action mechanism and its potential advantages in clinical applications. Additionally, we discuss the challenges and future directions for SMaRT therapy, emphasizing the need for further research to optimize its efficacy and safety. This review aims to provide a comprehensive overview of current and emerging therapies for HD, with a focus on the innovative potential of SMaRT. [ABSTRACT FROM AUTHOR]

Background: A connection has been established between ocular structural changes and various neurodegenerative diseases. Several studies utilizing optical coherence tomography (OCT) have detected signs of ocular structural alterations among individuals with Huntington's disease (HD). The inconsistent results reported in the literature regarding alterations in the retina and choroid encouraged us to conduct this systematic review and meta-analysis to accumulate the findings. Methods: A systematic search was carried out in three electronic databases (PubMed, Embase, Scopus) to find studies reporting OCT measurements in HD cases compared with healthy controls (HC). A fixed-effects or random-effects meta-analysis was conducted according to the detected heterogeneity level. Furthermore, subgroup and sensitivity analyses, meta-regression, and quality assessment were performed. Results: Eleven studies were included in the systematic review and 9 studies with a total population of 452 participants (241 cases, and 211 HC) underwent meta-analysis. Results of the analysis denoted that subfoveal choroid had a significantly reduced thickness in HD eyes compared to HC (p < 0.0001). Moreover, our analysis indicated that HD cases had a significantly thinner average (p = 0.0130) and temporal peripapillary retinal nerve fiber layer (pRNFL) (p = 0.0012) than HC. However, subjects with pre-HD had insignificant differences in average (p = 0.44) and temporal pRNFL thickness (p = 0.33) with the HC group. Conclusion: Results of the current systematic review and meta-analysis revealed the significant thinning of average and temporal pRNFL and subfoveal choroid in HD compared to HC. However, OCT currently might be considered insensitive to be applied in the pre-HD population at least until further longitudinal investigations considering variables such as the duration between OCT measurement and disease onset validating OCT as a routine diagnostic tool in HD clinics. [ABSTRACT FROM AUTHOR]

• A selective agonist of GPCR LPA3 is produced by Bacillus velezensis ADS024. • Oleoyl-LPA and an extract of ADS024 promote LPA3 recruitment of 14–3-3 proteins. • ADS024 modifies cell-surface expression of LPA3 on immune cells in a MOG-EAE model. • ADS024 is efficacious in neuroinflammatory disease models of PD, HD, MS, ALS, CIPN. • Broad efficacy of ADS024 suggests a common anti-neuroinflammatory mechanism. Neuroinflammation is a common component of neurological disorders. In the gut-brain-immune axis, bacteria and their metabolites are now thought to play a role in the modulation of the nervous and immune systems which may impact neuroinflammation. In this respect, commensal bacteria of humans have recently been shown to produce metabolites that mimic endogenous G-protein coupled receptor (GPCR) ligands. To date, it has not been established whether plant commensal bacteria, which may be ingested by animals including humans, can impact the gut-brain-immune axis via GPCR agonism. We screened an isopropanol (IPA) extract of the plant commensal Bacillus velezensis ADS024, a non-engrafting live biotherapeutic product (LBP) with anti-inflammatory properties isolated from human feces, against a panel of 168 GPCRs and identified strong agonism of the lysophosphatidic acid (LPA) receptor LPA3. The ADS024 IPA extracted material (ADS024-IPA) did not agonize LPA2, and only very weakly agonized LPA1. The agonism of LPA3 was inhibited by the reversible LPA1/3 antagonist Ki16425. ADS024-IPA signaled downstream of LPA3 through G-protein-induced calcium release, recruitment of β-arrestin, and recruitment of the neurodegeneration-associated proteins 14–3-3γ, ε and ζ but did not recruit the β isoform. Since LPA3 agonism was previously indirectly implicated in the reduction of pathology in models of Parkinson's disease (PD) and multiple sclerosis (MS) by use of the nonselective antagonist Ki16425, and since we identified an LPA3-specific agonist within ADS024, we sought to examine whether LPA3 might indeed be part of a broad underlying mechanism to control neuroinflammation. We tested oral treatment of ADS024 in multiple models of neuroinflammatory diseases using three models of PD, two models of MS, and a model each of amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and chemo-induced peripheral neuropathy (CIPN). ADS024 treatment improved model-specific functional effects including improvements in motor movement, breathing and swallowing, and allodynia suggesting that ADS024 treatment impacted a universal underlying neuroinflammatory mechanism regardless of the initiating cause of disease. We used the MOG-EAE mouse model to examine early events after disease initiation and found that ADS024 attenuated the increase in circulating lymphocytes and changes in neutrophil subtypes, and ADS024 attenuated the early loss of cell-surface LPA3 receptor expression on circulating white blood cells. ADS024 efficacy was partially inhibited by Ki16425 in vivo suggesting LPA3 may be part of its mechanism. Altogether, these data suggest that ADS024 and its LPA3 agonism activity should be investigated further as a possible treatment for diseases with a neuroinflammatory component. [ABSTRACT FROM AUTHOR]

The basal ganglia (BG) in the brain exhibit diverse functions for motor, cognition, and emotion. Such BG functions could be made via competitive harmony between the two competing pathways, direct pathway (DP) (facilitating movement) and indirect pathway (IP) (suppressing movement). As a result of break-up of harmony between DP and IP, there appear pathological states with disorder for movement, cognition, and psychiatry. In this paper, we are concerned about the Huntington's disease (HD), which is a genetic neurodegenerative disorder causing involuntary movement and severe cognitive and psychiatric symptoms. For the HD, the number of D2 SPNs ( N D 2 ) is decreased due to degenerative loss, and hence, by decreasing x D 2 (fraction of N D 2 ), we investigate break-up of harmony between DP and IP in terms of their competition degree C d , given by the ratio of strength of DP ( S DP ) to strength of IP ( S IP ) (i.e., C d = S DP / S IP ). In the case of HD, the IP is under-active, in contrast to the case of Parkinson's disease with over-active IP, which results in increase in C d (from the normal value). Thus, hyperkinetic dyskinesia such as chorea (involuntary jerky movement) occurs. We also investigate treatment of HD, based on optogenetics and GP ablation, by increasing strength of IP, resulting in recovery of harmony between DP and IP. Finally, we study effect of loss of healthy synapses of all the BG cells on HD. Due to loss of healthy synapses, disharmony between DP and IP increases, leading to worsen symptoms of the HD. [ABSTRACT FROM AUTHOR]

Background: Pathophysiological changes of Huntington's disease (HD) can precede symptom onset by decades. Robust imaging biomarkers are needed to monitor HD progression, especially before the clinical onset. Purpose: To investigate iron dysregulation and microstructure alterations in subcortical regions as HD imaging biomarkers, and to associate such alterations with motor and cognitive impairments. Study Type: Prospective. Population: Fourteen individuals with premanifest HD (38.0 ± 11.0 years, 9 females; far‐from‐onset N = 6, near‐onset N = 8), 21 manifest HD patients (49.1 ± 12.1 years, 11 females), and 33 age‐matched healthy controls (43.9 ± 12.2 years, 17 females). Field Strength/Sequence: 7 T, T1‐weighted imaging, quantitative susceptibility mapping, and diffusion tensor imaging. Assessment: Volume, susceptibility, fractional anisotropy (FA), and mean diffusivity (MD) within subcortical brain structures were compared across groups, used to establish HD classification models, and correlated to clinical measures and cognitive assessments. Statistical Tests: Generalized linear model, multivariate logistic regression, receiver operating characteristics with the area under the curve (AUC), and likelihood ratio test comparing a volumetric model to one that also includes susceptibility and diffusion metrics, Wilcoxon paired signed‐rank test, and Pearson's correlation. A P‐value <0.05 after Benjamini–Hochberg correction was considered statistically significant. Results: Significantly higher striatal susceptibility and FA were found in premanifest and manifest HD preceding atrophy, even in far‐from‐onset premanifest HD compared to controls (putamen susceptibility: 0.027 ± 0.022 vs. 0.018 ± 0.013 ppm; FA: 0.358 ± 0.048 vs. 0.313 ± 0.039). The model with additional susceptibility, FA, and MD features showed higher AUC compared to volume features alone when differentiating premanifest HD from HC (0.83 vs. 0.66), and manifest from premanifest HD (0.94 vs. 0.83). Higher striatal susceptibility significantly correlated with cognitive deterioration in HD (executive function: r = −0.600; socioemotional function: r = −0.486). Data Conclusion: 7 T MRI revealed iron dysregulation and microstructure alterations with HD progression, which could precede volume loss, provide added value to HD differentiation, and might be associated with cognitive changes. Evidence Level: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) can provide corroborative data on neurophysiological alterations in Huntington's disease (HD). However, the alterations in EEG and fMRI resting-state functional connectivity (rsFC), as well as their interrelations, at different stages of HD remain insufficiently investigated. This study aimed to identify neurophysiological alterations in individuals with preclinical HD (preHD) and early manifest HD (EMHD) by analyzing EEG and fMRI rsFC and examining their interrelationships. We found significant differences in EEG power between preHD individuals and healthy controls (HC), with a decrease in power in a specific frequency range at the theta-alpha border and slow alpha activity. In EMHD patients, in addition to the decrease in power in the 7--9 Hz range, a reduction in power within the classic alpha band compared to HC was observed. The fMRI analysis revealed disrupted functional connectivity in various brain networks, particularly within frontal lobe, putamen-cortical, and cortico-cerebellar networks, in individuals with the HD mutation compared to HC. The analysis of the relationship between EEG and fMRI rsFC revealed an association between decreased alpha power, observed in individuals with EMHD, and increased connectivity in large-scale brain networks. These networks include putamen-cortical, DMN-related and cortico-hippocampal circuits. Overall, the findings suggest that EEG and fMRI provide valuable information for monitoring pathological processes during the development of HD. A decrease in inhibitory control within the putamen-cortical, DMN-related and cortico-hippocampal circuits, accompanied by a reduction in alpha and theta-alpha border oscillatory activity, could potentially contribute to cognitive decline in HD. [ABSTRACT FROM AUTHOR]

Background and objectives: The premanifest phase of Huntington's disease (HD) is characterized by the absence of motor symptoms and exhibits structural changes in imaging that precede clinical manifestation. This study aimed to analyze volumetric changes identified through brain magnetic resonance imaging (MRI) processed using artificial intelligence (AI) software in premanifest HD individuals, focusing on the relationship between CAG triplet expansion and structural biomarkers. Methods: The study included 36 individuals descending from families affected by HD in the Department of Atlántico. Sociodemographic data were collected, followed by peripheral blood sampling to extract genomic DNA for quantifying CAG trinucleotide repeats in the Huntingtin gene. Brain volumes were evaluated using AI software (Entelai/IMEXHS, v4.3.4) based on MRI volumetric images. Correlations between brain volumes and variables such as age, sex, and disease status were determined. All analyses were conducted using SPSS (v. IBM SPSS Statistics 26), with significance set at p < 0.05. Results: The analysis of brain volumes according to CAG repeat expansion shows that individuals with ≥40 repeats evidence significant increases in cerebrospinal fluid (CSF) volume and subcortical structures such as the amygdalae and left caudate nucleus, along with marked reductions in cerebral white matter, the cerebellum, brainstem, and left pallidum. In contrast, those with <40 repeats show minimal or moderate volumetric changes, primarily in white matter and CSF. Conclusions: These findings suggest that CAG expansion selectively impacts key brain regions, potentially influencing the progression of Huntington's disease, and that AI in neuroimaging could identify structural biomarkers long before clinical symptoms appear. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorder refers to malfunctioning of neurons their degradation leading to death of neurons. Among various neurodegenerative disorders APHD (Alzheimer's, Parkinson's, and Huntington's Disease) are particularly concerning due to their progressive and debilitating nature. The therapeutic agent used for treatment and management of APHD often show unsatisfactory clinical outcome owing to poor solubility and limited permeability across blood brain barrier (BBB). The nose-to brain delivery can overcome this BBB challenge as it can transport drug directly to brain though olfactory pathways bypassing BBB. Additionally, the nanotechnology has emerged as a cutting-edge methodology to address this issue and specifically mucoadhesive micro/nanoemulsion can improve the overall performance of the drug when administered intranasally. Beyond the therapy neurotechnology has emerged as are revolutionary AI-driven BCI (Brain computer interface) aimed to restore independence in patients with function loss due to neuron degeneration/death. A promising BCI Neuralink has been recently explored for clinical trials and results revealed that a quadriplegia bearing person with implanted Neuralink chip was able to perform few normal functions of daily routine such as playing online games, text messaging, reading, and learning foreign languages online through accessing the particular websites. This review will discuss the fundamental concepts of neurodegeneration, application of micro/nanoemulsion through intranasal route and integration of neurotechnology for the management and treatment of APHD. [ABSTRACT FROM AUTHOR]

Huntington's Disease (HD) is a hereditary neurodegenerative disorder that is primarily manifested by motor, cognitive, and behavioral symptoms due to an expanded CAG trinucleotide repeat in the HTT gene. Currently, most of the therapeutic strategies in HD are largely centered on the pharmacological management of the symptoms. These treatments are linked to some disadvantages such as being partially effective, having adverse effects, and their inability to alter the natural course of the disease. Recent developments in HD research are exploring the use of novel pharmacological agents, nanoparticles, cell therapies, gene therapies, and RNA-based therapies, which have shown promise in preclinical and clinical studies. This literature review explores various aspects of HD, from its pathogenesis and etiology to emerging novel approaches for its treatment. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals' striata that mimic HD. The role of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet. Aim: This study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations. Methods: Male Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1β, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis. Results: PTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype. Conclusion: PTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling. [ABSTRACT FROM AUTHOR]

Introduction: Huntington's disease (HD) is a hereditary neurodegenerative disorder that primarily affects the striatum, a brain region responsible for movement control. The disease is characterized by the mutant huntingtin (mHtt) proteins with an extended polyQ stretch, which are prone to aggregation. These mHtt aggregates accumulate in neurons and are the primary cause of the neuropathology associated with HD. To date, no effective cure for HD has been developed. Methods: The immortalized STHdhQ111/Q111 striatal cell line, the mHtt-transfected wild-type STHdhQ7/Q7 striatal cell line, and N2a cells were used as Huntington's disease cell models. Flow cytometry was used to assess cellular reactive oxygen species and transfection efficiency. The CCK-8 assay was used to measure cell viability, while fluorescence microscopy was used to quantify aggregates. Immunoblotting analyses were used to evaluate the effects on protein expression. Results: Polyphenols are natural antioxidants that offer neuroprotection in neurological disorders. In this study, we provide evidence that oleuropein, the primary polyphenol in olive leaves and olive oil, enhances cell viability in HD cell models, including. STHdhQ7/Q7 STHdhQ7/Q7 striatal cells, N2a cells ectopically expressing the truncated mHtt, and STHdhQ111/Q111 striatal cells expressing the full-length mHtt. Oleuropein effectively reduced both soluble and aggregated forms of mHtt protein in these HD model cells. Notably, the reduction of mHtt aggregates associated with oleuropein was linked to increased proteasome activity rather than changes in autophagic flux. Oleuropein seems to modulate proteasome activity through an unidentified pathway, as it did not affect the 20S proteasome catalytic β subunits, the proteasome regulator PA28γ, or multiple MAPK pathways. Discussion: We demonstrated that oleuropein enhances the degradation of mHtt by increasing proteasomal protease activities and alleviates mHtt-induced cytotoxicity. Hence, we propose that oleuropein and potentially other polyphenols hold promise as a candidate for alleviating Huntington's disease. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3'-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients' brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Depletion of PFKFB3 markedly abrogates PNKP activity without changing its protein level. Notably, the levels of both PFKFB3 and its product fructose-2,6 bisphosphate (F2,6BP), an allosteric modulator of glycolysis, are significantly lower in the nuclear extracts of postmortem brain tissues of HD and SCA3 patients. Supplementation of F2,6BP restored PNKP activity in the nuclear extracts of patients' brain. Moreover, intracellular delivery of F2,6BP restored both the activity of PNKP and the integrity of transcribed genome in neuronal cells derived from the striatum of the HD mouse. Importantly, supplementing F2,6BP rescued the HD phenotype in Drosophila, suggesting F2,6BP to serve in vivo as a cofactor for the proper functionality of PNKP and thereby, of brain health. Our results thus provide a compelling rationale for exploring the therapeutic use of F2,6BP and structurally related compounds for treating polyQ diseases. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by neuropsychiatric symptoms including chorea, dementia, and depression. It is inherited in an autosomal dominant fashion and exhibits anticipation leading to earlier and more severe symptoms in the affected offspring of a patient. With a much lower prevalence in Asia than in Europe and other parts of the world, its diagnosis can be missed easily in the early stages due to mildness of the symptoms and significant overlap between its symptoms and those of other diseases. We present the case of a 38-year-old male of Pashtun ethnicity presenting with mild cognitive impairment and clumsiness who was eventually diagnosed with HD, but his mild clinical features, no documented history of HD in his parents, and his relatively young age coupled with the relatively low prevalence of HD in his geographical location presented a significant challenge in our diagnosis of his condition. This case underscores the importance of keeping a high clinical suspicion for HD in patients with chorea despite a negative parental history, especially in resource-limited areas where the parents may have gone undiagnosed and highlights the need for further research on HD's prevalence in different parts of the world as well as the barriers to its diagnosis. [ABSTRACT FROM AUTHOR]

There is evidence for dysregulated cholesterol homeostasis in Huntington’s disease (HD). The brain-specific cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-OHC) is decreased in manifest HD. 24(S)-OHC is an endogenous positive allosteric modulator (PAM) of the N-methyl-D-aspartate (NMDA) receptor, suggesting lower 24(S)-OHC may contribute to NMDA receptor hypofunction in HD. We hypothesized changes in 24(S)-OHC would be associated with cognitive impairment in early HD.To determine the interactions between oxysterols (24(S)-OHC, 25-OHC, and 27-OHC) at the NMDA receptor, the plasma levels of these oxysterols, and how these levels relate to cognitive performance.An in vitro competition assay was used to evaluate interactions at the NMDA receptor, liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) was used to measure plasma 24(S)-OHC, 25-OHC, and 27-OHC levels, and correlation analyses investigated their relationship to performance on cognitive endpoints in TRACK and ENROLL-HD (NCT01574053).In vitro, 25-OHC and 27-OHC attenuated the PAM activity of 24(S)-OHC on the NMDA receptor. Lower plasma 24(S)-OHC levels and 24(S)/25-OHC ratios were detected in participants with early HD. Moderate and consistent associations were detected between plasma 24(S)/25-OHC ratio and performance on Stroop color naming, symbol digit modality, Trails A/B, and emotion recognition. Little association was observed between the ratio and psychiatric or motor endpoints, suggesting specificity for the relationship to cognitive performance.Our findings support growing evidence for dysregulated CNS cholesterol homeostasis in HD, demonstrate a relationship between changes in oxysterols and cognitive performance in HD, and propose that NMDA receptor hypofunction may contribute to cognitive impairment in HD. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a rare neurodegenerative disease caused due to aggregation of Huntingtin (HTT) protein. This study involves the cloning of 40 DnaJ chaperones from Drosophila, and overexpressing them in yeasts and fly models of HD. Accordingly, DnaJ chaperones were catalogued as enhancers or suppressors based on their growth phenotypes and aggregation properties. 2 of the chaperones that came up as targets were CG5001 and P58IPK. Protein aggregation and slow growth phenotype was rescued in yeasts, S2 cells, and Drosophila transgenic lines of HTT103Q with these overexpressed chaperones. Since DnaJ chaperones have protein sequence similarity across species, they can be used as possible tools to combat the effects of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Aims: The study aimed to evaluate the potential benefits of luteolin treatment in Huntington's disease (HD), an inherited progressive neurodegenerative disorder. Methods: HD N171‐82Q transgenic and WT mice received luteolin or vehicle for treatment at 6 weeks of age. The mice's body weight changes and survival rates were monitored throughout the study, and a series of motor functional tests were conducted. Serum level of the marker NfL was also determined. Immunohistochemical staining and western blotting were utilized to assess the expression of huntingtin aggregates. Results: Luteolin treatment enhanced survival and prevented weight loss in HD mice compared to the vehicle‐treated HD group. Furthermore, the luteolin‐treated HD mice exhibited enhanced motor coordination and balance and significantly reduced motor dysfunction. Also, luteolin decreased serum NfL levels in HD mice. Notably, the accumulation of huntingtin aggregates was significantly reduced in the brain's cortex, hippocampus, and striatum of luteolin‐treated HD mice compared to the vehicle‐treated HD group. Conclusion: Luteolin holds promise as a therapeutic agent for improving survival outcomes, managing motor dysfunction, and reducing huntingtin aggregates in HD. The findings are of significance as currently, there are no approved therapeutic interventions that reverse HD pathology or slow down its progression. [ABSTRACT FROM AUTHOR]

Huntington's disease and juvenile-onset schizophrenia have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between Huntington's disease and schizophrenia hGPCs yet distinct from normal controls that included 174 highly connected genes in the shared disease-associated network, focusing on genes involved in synaptic signalling. These synaptic genes were largely suppressed in both schizophrenia and Huntington's disease hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3 , a modulator of glutamatergic synapses, was notably suppressed in both schizophrenia and Huntington's disease hGPCs. Chromatin immunoprecipitation sequencing confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3 , whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signalling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, Huntington's disease and schizophrenia. [ABSTRACT FROM AUTHOR]

Polyglutamine (polyQ) disorders are monogenic neurodegenerative disorders. Currently, no therapies are available for this complex group of disorders. Here, we aim to provide an overview of recent promising preclinical studies and the ongoing clinical trials focusing on molecular therapies for polyQ disorders. [ABSTRACT FROM AUTHOR]

This study sought to investigate if there was a significant difference between the Huntington's Disease gene expansion carriers who were impaired on the cognitive domains, social cognition and executive functions. Also, it was investigated which of the cognitive domains could predict the decrease in total functional capacity over a 6-year follow-up period. Premanifest and motor-manifest Huntington's Disease gene expansion carriers (N = 98), were examined with a neurological and neuropsychological examination at Time 1 (year 2012–2013). Regression-based normative data was used to classify impairments on the two cognitive domains. Follow-up participants (N = 80) had their functional capacity reexamined at Time 2 (year 2018–2020), to examine which cognitive domain could predict the decrease in functional capacity over the 6-year follow-up. More than 50% of the participants were impaired on the domain of social cognition. These participants were significantly different from the participants who were impaired on executive functions. The motor function and impairments on social cognition significantly predicted the decline in functional capacity. The Emotion Hexagon test was the only significant social cognitive task, that predicted the decline in functional capacity. Social cognition includes unique and separate functions in Huntington's Disease, unaffected by executive functions. This study emphasizes the importance of regular assessment of social cognition in Huntington's Disease and the clinical relevance of impaired social cognitive function. [ABSTRACT FROM AUTHOR]

Epigenetic modulations play a major role in gene expression and thus are responsible for various physiological changes including age-associated neurological disorders. Neurodegenerative diseases such as Alzheimer's (AD), Parkinson's (PD), Huntington's disease (HD), although symptomatically different, may share common underlying mechanisms. Most neurodegenerative diseases are associated with increased oxidative stress, aggregation of certain proteins, mitochondrial dysfunction, inactivation/dysregulation of protein degradation machinery, DNA damage and cell excitotoxicity. Epigenetic modulations has been reported to play a significant role in onset and progression of neurodegenerative diseases by regulating these processes. Previous studies have highlighted the marked antioxidant and neuroprotective abilities of polyphenols such as curcumin, by increased activity of detoxification systems like superoxide dismutase (SOD), catalase or glutathione peroxidase. The role of curcumin as an epigenetic modulator in neurological disorders and neuroinflammation apart from other chronic diseases have also been reported by a few groups. Nonetheless, the evidences for the role of curcumin mediated epigenetic modulation in its neuroprotective ability are still limited. This review summarizes the current knowledge of the role of mitochondrial dysfunction, epigenetic modulations and mitoepigenetics in age-associated neurological disorders such as PD, AD, HD, Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), and describes the neuroprotective effects of curcumin in the treatment and/or prevention of these neurodegenerative diseases by regulation of the epigenetic machinery. [ABSTRACT FROM AUTHOR]