LAUSR

Significance We have developed an approach to define the size of small aggregates involved in neurodegenerative disorders at ∼4 nm precision in live cells and in pathological model mouse tissues. We show that aggregates below 450 nm are harmful and readily penetrate cells. Once they invade cells, aggregates are surrounded by proteasomes, which are responsible for protein destruction, leading to aggregate removal. We further isolated aggregates from Parkinson’s disease and dementia with Lewy bodies donors, two distinct diseases that involve aggregates assembled from the same protein, α-synuclein, to validate that our 450 nm aggregate definition correlates with the measured toxicity level and reveal that different synucleinopathies have distinct toxicity profiles. Our method offers possibilities to strategize for individual disease prognosis.