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.

Poly-ADP-ribosylation (PARylation), catalyzed by the enzyme PARP1, involves the addition of poly-ADP-ribose polymers (PAR) and has been associated with α-synuclein aggregation in Parkinson’s disease (PD) models. This study aimed to unravel the role of PARylation in α-synuclein aggregation and neuronal cell death in the complex environment of post-mortem human PD brains. Using high-resolution imaging and 3D reconstruction analysis, we observed that PAR accumulate in the cytoplasm in regions affected by PD pathology, preceding the formation of α-synuclein oligomers. Additionally, we found that PAR and stress granules contribute to the formation of Lewy bodies. Increased colocalization of PAR with mitochondria in the substantia nigra of PD patients, along with the presence of PAR-positive condensed DNA, further suggests a role in neuronal cell death. Collectively, our findings reveal a critical involvement of PARylation in the pathological mechanisms underlying neurodegeneration in PD and position PARylation as a potential therapeutic target. GRAPHICAL

Pathological aggregation of α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), but increasing evidence indicates that αSyn deposits extend beyond the central nervous system to peripheral tissues, including the skin. In PD patients, cutaneous αSyn accumulation has been associated with seborrheic dermatitis (SD), a chronic inflammatory condition linked to sebocyte dysfunction and altered sebum production. Marked differences in sebum composition between PD patients and healthy controls have been described. We aimed to investigate whether pathological αSyn could contribute to dysregulated sebum production and composition by assessing key markers of sebocyte differentiation and lipogenesis in human sebaceous gland cells and skin biopsies from PD patients (n = 5) and matched controls (n = 5) without clinically recorded SD. O-αSyn exposure of immortalized sebaceous gland cells (SZ95) altered the transcriptional programs related to sebocyte differentiation, inflammation, metabolism, and lipogenesis. Consistently, protein markers of mid-to-late sebocyte differentiation were increased. Upregulation of PLIN2, together with elevated PPARγ, SREBP1, SCD1, and FADS2, indicated progression toward a mature and lipid-producing phenotype characterized by enhanced accumulation of neutral lipids within lipid droplets. Lipidomic profiling revealed remodeling of multiple lipid classes, with increases in triglycerides, ceramides, and selected phospholipids. Increased expression of PLIN2 and PPARγ was also observed in sebaceous glands from PD skin biopsies compared to controls. Collectively, our findings indicate that O-αSyn exposure is associated with molecular changes consistent with altered sebocyte differentiation and lipid remodeling. These results support a potential association between αSyn and lipid dysregulation in sebocytes and suggest that these cells may represent unrecognized peripheral targets of αSyn.