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 calcin
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.65
Evidence
0.72
Novelty
0.70
Feasibility
0.80
Impact
0.75
Druggability
0.00
Safety
0.00
Competition
0.00
Data
0.00
Reproducible
0.40
KG Connect
0.54
Score Breakdown
Dimension
SNCA Oligomers Sequester TFEB
Mechanistic
0.650
Evidence
0.720
Novelty
0.700
Feasibility
0.800
Impact
0.750
Druggability
0.000
Safety
0.000
Competition
0.000
Data
0.000
Reproducible
0.400
KG Connect
0.540
Evidence
SNCA Oligomers Sequester TFEB Phosphatases to Create a Phosp