Lewy Body-like α-Synuclein Aggregates Resist Degradation and Impair Macroautophagy

Cytoplasmic alpha-synuclein (alpha-syn) aggregates, referred to as Lewy bodies, are pathological hallmarks of a number of neurodegenerative diseases, most notably Parkinson disease. Activation of macroautophagy is suggested to facilitate degradation of certain proteinaceous inclusions, but it is unclear if this pathway is capable of degrading alpha-syn aggregates. Here, we examined this issue by utilizing cellular models in which intracellular Lewy body-like alpha-syn inclusions accumulate after internalization of pre-formed alpha-syn fibrils into alpha-syn-expressing HEK293 cells or cultured primary neurons. We demonstrate that alpha-syn inclusions cannot be effectively degraded, even though they co-localize with essential components of both the autophagic and proteasomal protein degradation pathways. The alpha-syn aggregates persist even after soluble alpha-syn levels have been substantially reduced, suggesting that once formed, the alpha-syn inclusions are refractory to clearance. Importantly, we also find that alpha-syn aggregates impair overall macroautophagy by reducing autophagosome clearance, which may contribute to the increased cell death that is observed in aggregate-bearing cells.