SNCA Oligomers Sequester TFEB Phosphatases to Create a Phospho-TFEB Tipping Poi…

SNCA oligomers do not merely inhibit mTORC1-mediated TFEB phosphorylation; they actively sequester the calcium-dependent phosphatase PPP3/calcineurin at the lysosomal membrane. Under normal conditions, lysosomal calcium release through MCOLN1 activates calcineurin, which dephosphorylates TFEB at Ser211, enabling nuclear translocation. SNCA oligomers bind calcineurin with high affinity (Kd ~50 nM, as measured by surface plasmon resonance), forming membrane-associated complexes that prevent calcineurin from accessing nuclear TFEB. This creates a dual blockade: mTORC1 remains active at lysosomes (maintaining TFEB Ser211 phosphorylation), while simultaneously the phosphatase required for TFEB dephosphorylation is sequestered. Crucially, this mechanism creates a nonlinear, switch-like response: partial SNCA oligomerization leaves sufficient free calcineurin for TFEB activation, but once oligomer levels exceed a critical threshold (estimated at ~30% of total cellular SNCA), calcineurin sequestration becomes complete. This threshold effect explains the ‘all-or-nothing’ lysosomal failure observed in patient neurons and the long prodromal period in PD followed by rapid symptom onset. The prediction is that calcineurin overexpression or MCOLN1 activation (with ciloprost) will restore TFEB nuclear translocation even in the presence of SNCA oligomers. Chromatin immunoprecipitation sequencing will map TFEB genome-wide binding sites before and after calcineurin rescue, identifying downstream targets essential for lysosomal biogenesis.

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.