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α-synuclein oligomers within synaptic terminals of autonomic fibers of the skin reliably discriminate Parkinson's disease (PD) patients from healthy controls. Nonetheless, the prognostic role of oligomers for disease progression is unknown. We explored whether α-synuclein oligomers evaluated as proximity ligation assay (PLA) score may predict the worsening of cognitive functions in patients with Parkinson's disease. Thirty-four patients with PD and thirty-four healthy controls (HC), matched 1:1 for age and sex, were enrolled. Patients with PD underwent baseline skin biopsy and an assessment of cognitive domains including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clock Drawing Test, and Frontal Assessment Battery. At the last follow-up visit available, patients were either cognitively stable (PD-CS) or cognitively deteriorated (PD-CD). α-synuclein oligomers were quantified as PLA scores. Differences between groups were assessed, controlling for potential confounders. The relationship between skin biopsy measures and cognitive changes was explored using correlation and multivariable regression analyses. The discrimination power of the PLA score was assessed via ROC curve. To elucidate the relationship between skin biopsy and longitudinal cognitive measures, we conducted multivariable regression analyses using delta scores of cognitive tests (Δ) as dependent variables. We found that PD-CD had higher baseline PLA scores than PD-CS (p = 0.0003), and they were correctly identified in the ROC curve analysis (AUC = 0.872, p = 0.0003). Furthermore, ANCOVA analysis with Bonferroni correction, considering all groups (PD-CS, PD-CD, and HC), showed significant differences between PD-CS and PD-CD (p = 0.003), PD-CS and HC (p = 0.002), and PD-CD and HC (p < 0.001). In the regression model using ΔMMSE as the dependent variable, the PLA score was found to be a significant predictor (β = −0.441, p = 0.016). Similar results were observed when evaluating the model with ΔMoCA (β = −0.378, p = 0.042). In conclusion, patients with Parkinson's disease with higher α-synuclein burden in the peripheral nervous system may be more susceptible to cognitive decline. [ABSTRACT FROM AUTHOR]

The main genetic risk factors for Parkinson's disease (PD) are presently represented by variants in GBA1 gene encoding for the β‐glucocerebrosidase (GCase). Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting GBA1‐associated PD (GBA1‐PD) is a current challenge. We previously demonstrated that α‐synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross‐sectional study investigates an unexplored cohort of GBA1‐PD (n = 27) compared to 28 HC, and 36 iPD cases to (i) analyze α‐synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific GBA1 mutations. PLA score discriminates GBA1‐PD from HC with sensitivity = 88.9% (95% CI 70.84–97.65), specificity = 88.5% (95% CI 69.85–97.55), and PPV = 88.9% (95% CI 73.24–95.90), AUC value = 0.927 (95% CI 0.859–0.996). No difference was found between GBA1‐PD patients and iPD, suggesting a common pathological pathway based on α‐synuclein oligomers. GCase score did not differ in GBA1‐PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in GBA1‐PD compared to iPD and HC (P < 0.0001). Employing ROC curve to discriminate GBA1‐PD from iPD, we found an AUC value for synaptic density = 0.855 (95% CI 0.749–0.961) with sensitivity = 85.2% (95% CI 66.27%–95.81%), specificity = 77.1% (95% CI 59.86%–89.58%), and PPV = 74.19% (60.53%–84.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing GBA1‐PD from iPD and to their potential to stratify and monitor patients in the context of new pathway‐specific therapeutic options. [ABSTRACT FROM AUTHOR]

Emerging evidence supports that altered α-tubulin acetylation occurs in Parkinson's disease (PD), a neurodegenerative disorder characterized by the deposition of α-synuclein fibrillary aggregates within Lewy bodies and nigrostriatal neuron degeneration. Nevertheless, studies addressing the interplay between α-tubulin acetylation and α-synuclein are lacking. Here, we investigated the relationship between α-synuclein and microtubules in primary midbrain murine neurons and the substantia nigra of post-mortem human brains. Taking advantage of immunofluorescence and Proximity Ligation Assay (PLA), a method allowing us to visualize protein–protein interactions in situ, combined with confocal and super-resolution microscopy, we found that α-synuclein and acetylated α-tubulin colocalized and were in close proximity. Next, we employed an α-synuclein overexpressing cellular model and tested the role of α-tubulin acetylation in α-synuclein oligomer formation. We used the α-tubulin deacetylase HDAC6 inhibitor Tubacin to modulate α-tubulin acetylation, and we evaluated the presence of α-synuclein oligomers by PLA. We found that the increase in acetylated α-tubulin significantly induced α-synuclein oligomerization. In conclusion, we unraveled the link between acetylated α-tubulin and α-synuclein and demonstrated that α-tubulin acetylation could trigger the early step of α-synuclein aggregation. These data suggest that the proper regulation of α-tubulin acetylation might be considered a therapeutic strategy to take on PD. [ABSTRACT FROM AUTHOR]

HDAC6 is a unique histone deacetylase that targets cytoplasmic non-histone proteins and has a specific ubiquitin-binding activity. Both of these activities are required for HDAC6-mediated formation of aggresomes, which contain misfolded proteins that will ultimately be degraded via autophagy. HDAC6 deacetylase activity is increased following phosphorylation on serine 22 (phospho-HDAC6). In human, HDAC6 localizes in neuronal Lewy bodies in Parkinson's disease (PD) and in oligodendrocytic Papp–Lantos bodies in multiple system atrophy (MSA). However, the expression of phospho-HDAC6 in post-mortem human brains is currently unexplored. Here, we evaluate and compare the distribution of HDAC6 and its phosphorylated form in human brains obtained from patients affected by three forms of parkinsonism: two synucleinopathies (PD and MSA) and a tauopathy (progressive supranuclear palsy, PSP). We find that both HDAC6 and its phosphorylated form localize with pathological protein aggregates, including α-synuclein-positive Lewy bodies in PD and Papp–Lantos bodies in MSA, and phospho-tau-positive neurofibrillary tangles in PSP. We further find a direct interaction of HDAC6 with α-synuclein with proximity ligation assay (PLA) in neuronal cell of PD patients. Taken together, our findings suggest that both HDAC6 and phospho-HDAC6 regulate the homeostasis of intra-neuronal proteins in parkinsonism. [ABSTRACT FROM AUTHOR]

Alpha-synuclein inclusions are the distinctive trait of brain areas affected by neurodegeneration in Parkinson's disease (PD). Nevertheless, PD is now considered as a multisystemic disorder, since alpha-synuclein pathology has been described also outside the central nervous system. In this regard, the early, non-motor autonomic symptoms point out an important role for the peripheral nervous system during disease progression. On this basis, we propose a review of the alpha-synuclein-related pathological processes observed at peripheral level in PD, starting from molecular mechanisms, through cellular processes to systemic modifications. We discuss their relevance in the etiopathogenesis of the disease, suggesting they are concurrent players in the development of PD, and that the periphery is an easily-accessible window to look at what is occurring in the central nervous system., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)