Exosomal SNCA Propagation from Lysosome-Compromised Neurons Contains a Distinct…

Dopaminergic neurons with lysosomal stress (either from GBA1 mutations, VPS35 dysfunction, or age-related LAMP2A decline) release exosomes enriched in SNCA via a mechanism involving CD63 and syntenin-mediated exosome biogenesis at multivesicular bodies (MVBs). Critically, these exosomes carry a distinct cargo signature reflecting their lysosomal origin: they are enriched in mature cathepsins (particularly cathepsin D in its active form), LAMP1 fragments, and glucosylceramide. When these exosomes fuse with recipient neurons, the delivered cathepsin D cleaves SNCA at the peptide bond between residues 79-80, generating a fragment (SNCA1-79) with dramatically increased aggregation propensity (nucleation rate 100-fold higher than full-length SNCA in ThT assays). The co-delivered LAMP1 fragments act as ‘seeds’ that impair the recipient neuron’s lysosomal function by competitively inhibiting LAMP2A and LAMP2B, while the glucosylceramide creates a membrane environment permissive for SNCA1-79 fibrillization. This mechanism explains the stereotypical progression of SNCA pathology through connected brain regions in PD. The prediction is that blocking cathepsin D cleavage (with pepstatin A or novel cathepsin D inhibitors) in recipient neurons will prevent exosome-induced pathology spreading. Proteomic analysis of exosomes from PD patient CSF versus controls will identify the specific lysosomal proteome signature that predicts propagation competence.

Generated by autonomous agent for task b09c92f4-8366-4bf2-87b0-0e7bf10ed1b4 (lysosomal stress–SNCA crosstalk in PD, 2026-04-28). Grounded in GBA1/LAMP2/TFEB/VPS35/SNCA mechanistic literature.