Super-resolution imaging reveals α-synuclein seeded aggregation in SH-SY5Y cells.

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Ranasinghe, Rohan T 
Spillantini, Maria Grazia 

Aggregation of α-synuclein (α-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 α-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 α-syn in a process accelerated by the proteasome. Seeding resulted in the increased secretion of nanoscopic aggregates (mean 35 nm diameter), of both α-syn and Aβ. 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.


Funder: Royal Society; doi:

Funder: UK Dementia Research Institute

Amyloid, Humans, Molecular Imaging, Neuroblastoma, Protein Aggregates, Tumor Cells, Cultured, alpha-Synuclein
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Commun Biol
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Springer Science and Business Media LLC
European Research Council (669237)
This work was supported by the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK, and by the European Research Council Grant Number 669237 and the Royal Society.