Study of alpha-synuclein and its catabolic pathways in ex vivo cells of patients with Parkinson’s disease

Parkinson’s disease (PD) is pathologically characterized by the presence of neuronal inclusions known as Lewy bodies, composed primarily of alpha-synuclein (asyn) aggregates. Emerging data indicate that a dysregulation of the autophagic-lysosomal pathway plays a critical pathogenic role in PD, favoring the intraneuronal accumulation of asyn and other neurotoxic proteins. Besides macroautophagy alterations, dysfunctions of chaperone-mediated autophagy (CMA), the main catabolic pathway for asyn, have been reported in post-mortem brain samples obtained from PD patients. To verify the presence of possible systemic alterations of CMA mirroring those observed in diseased brain areas, the expression of CMA effectors (lamp2A e hsc70) and substrates (asyn and MEF2D) was evaluated in peripheral blood mononuclear cells (PBMC) from PD patients and compared to healthy and neurological controls. Similar analyses are ongoing in fibroblast cell lines obtained from sporadic and familial (LRRK2 and SNCA mutant) PD patients obtained from the “Parkinson Institute Biobank” (Milan, http://www.parkinsonbiobank.com/). Results from this study will allow the identification of new possible PD biomarkers useful for early diagnosis, personalized therapy and monitoring of drug efficacy in clinical trials.