Super-Resolution Imaging Reveals Alpha-Synuclein Seeded Aggregation In Sh-Sy5y Cells

Aggregation of alpha -synuclein (alpha -syn) is closely linked to Parkinson's disease (PD) and the related synucleinopathies. Aggregates spread through the brain during the progression of PD, but the mechanism by which this occurs is still not known. One possibility is a self-propagating, templated-seeding mechanism, but this cannot be established without quantitative information about the efficiencies and rates of the key steps in the cellular process. To address this issue, we imaged the uptake and seeding of unlabeled exogenous alpha -syn fibrils by SH-SY5Y cells and the resulting secreted aggregates, using super-resolution microscopy. Externally-applied fibrils very inefficiently induced self-assembly of endogenous alpha -syn in a process accelerated by the proteasome. Seeding resulted in the increased secretion of nanoscopic aggregates (mean 35nm diameter), of both alpha -syn and A beta. Our results suggest that cells respond to seed-induced disruption of protein homeostasis predominantly by secreting nanoscopic aggregates; this mechanism may therefore be an important protective response by cells to protein aggregation. Jason Sang et al. use super-resolution microscopy to monitor alpha -synuclein aggregation and uptake in SH-SY5Y neuroblastoma cells. Their results suggest that cells secrete nanoscopic aggregates in response to disruption of protein homeostasis by these alpha -synuclein seeds, and may represent a protective response by cells to protein aggregation.