SNCA Oligomer Binding to LAMP2A Cytosolic Tail Prevents TorsinA-Mediated LAMP2A…

LAMP2A protein levels are regulated post-translationally by the AAA+ ATPase torsinA, which mediates extraction of aged or damaged LAMP2A from the lysosomal membrane for degradation. This torsinA-dependent turnover normally maintains a young pool of LAMP2A with high translocation competence. In PD, SNCA oligomers bind directly to the LAMP2A cytosolic domain (residues 1-24), physically blocking the torsinA recognition motif without affecting LAMP2A’s ability to form SNCA complexes. This creates a paradox: LAMP2A is functionally ‘frozen’ in a state capable of binding SNCA but incapable of translocating it, and simultaneously cannot be turned over. The stabilized LAMP2A-SNCA complex undergoes conformational changes that expose N-terminal epitopes, generating neoantigens recognized by autoantibodies in PD patient serum. Meanwhile, newly synthesized LAMP2A cannot accumulate because the surface pool is fully occupied. The prediction is that torsinA agonists (e.g., small molecules that enhance torsinA ATPase activity) will restore LAMP2A turnover, freeing receptors for SNCA degradation while eliminating the toxic stabilized complex. Cryo-EM structures of the LAMP2A-SNCA oligomer complex will reveal the binding interface and guide peptidomimetic design. Patient-derived neurons with GBA1 mutations will show elevated levels of stabilized LAMP2A-SNCA complexes by co-immunoprecipitation.

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.