SNCA Aggregation Hijacks the Endosomal Sorting Complex Required for Transport (…

The ESCRT machinery (particularly CHMP2B, TSG101, and ALIX) normally mediates budding of intraluminal vesicles into MVBs and resealing of damaged lysosomal membranes. In PD, phosphorylated SNCA (at Ser129) acts as a pathological ligand that recruits ESCRT-III components to lysosomal membranes via a novel phospho-dependent interaction with CHMP2B. Normally, LAMP2A coordinates this process by recruiting TSG101; however, in PD, hyperphosphorylated SNCA outcompetes LAMP2A for TSG101 binding. This redirects ESCRT machinery toward SNCA aggregates rather than membrane repair, causing accumulation of damaged lysosomal membranes and failed MVB maturation. The trapped MVBs cannot fuse with lysosomes, creating a compartment where SNCA continues to aggregate. VPS35 dysfunction exacerbates this by impairing retrieval of ESCRT components to the cytoplasm for recycling. The prediction is that blocking the SNCA- CHMP2B interaction (with cell-penetrating peptides targeting the CHMP2B-binding domain) will restore lysosomal membrane repair and MVB trafficking. Structured illumination microscopy will visualize the displacement of ESCRT components from lysosomes to SNCA aggregates in patient-derived neurons. Proximity ligation assays will confirm the phospho-dependent SNCA-CHMP2B complex in situ.

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.