IMPRiND partners BRFAA and CNRS established a cell model to assess aggregation and turnover of α-Synuclein (α-Syn) assemblies. Reporting in Journal of Neurochemistry, Pantazopoulou et al. used neuronally differentiated SH-SY5Y neuroblastoma cells with inducible expression of α-Syn and induced seeding of endogenous Proteinase K-resistant α-Syn species with the addition of α-Syn pre-formed fibrils (PFFs). Subsequently, the shutting down of the expression of α-Syn in this inducible cell model resulted in the clearance of α-Syn aggregates. Using this model, it was demonstrated that macroautophagy seems to serve as the major pathway for clearance of highly aggregated α-Syn assemblies whereas the Proteasome System is implicated in the degradation of phosphorylated at S129 α-Syn oligomers. These findings that different degradation pathways induce the clearance of distinct α-Syn aggregated species represent new and important insights into the biology of α-Syn aggregation and turnover.

This well established cell model can prove an essential tool to assess aggregation and turnover of α-Syn assemblies as well as the role of different post-translational modifications (i.e. phosphorylation, ubiquitylation, truncation, sumoylation) and their effect on oligomerization, and to further screen for modifiers affecting α-Syn aggregation, clearance, secretion and cell-to-cell transmission. A deeper understanding of the mechanisms underlying aggregation propensity and clearance may help design novel strategies for regulating the levels of toxic α-Syn conformers and eventually develop a treatment for PD and related synucleinopathies.

Different degradation pathways induce the clearance of distinct α-Syn aggregated species. Upon incubation with recombinant fibrils (PFFs), endogenous α-Syn aggregates are formed and Autophagy serves as the major pathway for clearance. pS129 α-Syn oligomers are apparent only upon incubation with high-dose PFFs, and the Proteasome system is implicated in the degradation process.

Tags: highlight