Distinct alpha ‐Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH‐SY5Y cells

AbstractA major pathological feature of Parkinson ’s disease (PD) is the aberrant accumulation of misfolded assemblies of alpha‐synuclein (α‐Syn). Protein clearance appears as a regulator of the ‘’α‐Syn burden” underlying PD pathogenesis. The picture emerging is that a combination of pathways with complementary roles, including the Proteasome System and the Autophagy‐Lysosome Pathway, contributes to the intracellular degradation ofα‐Syn. The current study addresses the mechanisms governing the degradation ofα‐Syn species seeded by exogenous fibrils in neuronally differentiated SH‐SY5Y neuroblastoma cells with inducible expression ofα‐Syn. Using humanα‐Syn recombinant fibrils (pre‐formed fibrils, PFFs), seeding and aggregation of endogenous Proteinase K (PK)‐resistantα‐Syn species occurs within a time frame of 6 days, and is still prominent after 12 days of PFF addition. Clearance ofα‐Syn assemblies in this inducible model was enhanced after switching offα‐Syn expression with doxycycline. Lysosomal inhibition led to accumulation of SDS‐solubleα‐Syn aggregates 6 days after PFF‐addition or when switching offα‐Syn expression. Additionally, the autophagic enhancer, rapamycin, induced the clearance ofα‐Syn aggregates 13 days post‐PFF addition, indicating that autophagy is the major pathway for aggregatedα‐Syn clearance. SDS‐soluble phosphorylatedα‐Syn at S129 was only apparent at 7 days of incubation with a higher ...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research