LAMP2A Liquid-Liquid Phase Separation Defects in Dopaminergic Neurons Create Selective Vulnerability to SNCA-Mediated CMA Blockade

LAMP2A exists in the lysosomal membrane as both monomers and higher-order oligomers that undergo liquid-liquid phase separation (LLPS) to form membrane microdomains essential for SNCA recognition and translocation into the lysosomal lumen. Recent biophysical studies demonstrate that LAMP2A’s cytosolic tail contains an intrinsically disordered region capable of mediating homotypic LLPS, creating lipid-raft-like microdomains enriched in chaperone-HSC70. In A9 dopaminergic neurons (vulnerable), LAMP2A undergoes age-dependent oxidation at cysteine residues (particularly Cysteine 50), which disrupts LLPS and reduces the formation of functional CMA translocation microdomains. This oxidation occurs at higher rates in these neurons due to their elevated cytosolic dopamine oxidation and mitochondrial ROS production. The phase-separated LAMP2A domains normally concentrate SNCA for unfolding and import; when these domains disassemble, SNCA instead accumulates at the lysosomal membrane surface where it forms toxic oligomers. The prediction is that cysteine-to-serine LAMP2A mutants resistant to oxidation will rescue CMA function in dopaminergic neurons. Super-resolution microscopy will reveal the loss of LAMP2A LLPS puncta in aged human PD substantia nigra neurons. Fluorescence recovery after photobleaching (FRAP) experiments in engineered liposomes will quantify the relationship between LAMP2A phase separation and SNCA import kinetics. This mechanism explains the selective vulnerability of A9 neurons independent of absolute LAMP2A expression levels.

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.