Glucocerebrosidase depletion enhances cell-to-cell transmission of α-synuclein

Deposition of alpha-synuclein aggregates occurs widely in the central and peripheral nervous systems in Parkinson's disease (PD). Although recent evidence has suggested that cell-to-cell transmission of alpha-synuclein aggregates is associated with the progression of PD, the mechanism by which alpha-synuclein aggregates spread remains undefined. Here, we show that alpha-synuclein aggregates are transmitted from cell to cell through a cycle involving uptake of external aggregates, co-aggregation with endogenous alpha-synuclein and exocytosis of the co-aggregates. Moreover, we find that glucocerebrosidase depletion, which has previously been strongly associated with PD and increased cognitive impairment, promotes propagation of alpha-synuclein aggregates. These studies define how alpha-synuclein aggregates spread among neuronal cells and may provide an explanation for how glucocerebrosidase mutations increase the risk of developing PD and other synucleinopathies.