Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission

TLDR

Alpha‑synuclein aggregation is central to Parkinson’s disease, and its direct transmission between neurons may drive disease spread through the nervous system. Exosomes from alpha‑synuclein‑overexpressing cells carry the protein and efficiently transfer it to healthy cells, and lysosomal dysfunction amplifies exosomal release and transmission, underscoring exosomes as key mediators and potential therapeutic targets in Parkinson’s disease.

Abstract

Alpha-synuclein aggregation plays a central role in Parkinson's disease pathology. Direct transmission of alpha-synuclein from pathologically affected to healthy unaffected neurons may be important in the anatomical spread of the disease through the nervous system. We have demonstrated that exosomes released from alpha-synuclein over-expressing SH-SY5Y cells contained alpha-synuclein and these exosomes were capable of efficiently transferring alpha-synuclein protein to normal SH-SY5Y cells. Moreover, the incubation of cells with ammonium chloride or bafilomycin A1 to produce the lysosomal dysfunction recently reported in Parkinson's disease led to an increase in the release of alpha-synuclein in exosomes and a concomitant increase in alpha-synuclein transmission to recipient cells. This study clearly demonstrates the importance of exosomes in both the release of alpha synuclein and its transmission between cells and suggests that factors associated with PD pathology accelerate this process. These mechanisms may play an important role in PD pathology and provide a suitable target for therapeutic intervention.