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
A9 dopaminergic neurons uniquely co-express TFEB and TFE3 at high levels, with TFE3 serving as a compensatory backup transcription factor for TFEB under lysosomal stress. In GBA1 deficiency, TFEB activation initially upregulates the CLEAR network to restore lysosomal biogenesis. However, in these neurons, this compensatory response fails because the newly synthesized LAMP2A protein cannot properly integrate into lysosomal membranes due to a concurrent defect in VPS35-mediated trafficking. The ac
Convergent vs Divergent Predictions
This summary checks where the selected hypotheses point toward the same target or mechanism, and where they pull in opposite directions.
TFEBLysosomal Stressneurodegeneration
Convergent signals
TFEB recurs across 2 selected hypotheses with aligned directionality in lysosomal stress.
Divergent signals
No direct polarity conflicts detected among the selected hypotheses.
Verdict Summary
5/11
dimensions won
SNCA Oligomers Sequester TFEB Phosphatas
3/11
dimensions won
GBA1 Loss Triggers a TFEB-to-TFE3 Compen
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.65
0.72
Evidence
0.72
0.65
Novelty
0.70
0.88
Feasibility
0.80
0.00
Impact
0.75
0.00
Druggability
0.00
0.00
Safety
0.00
0.00
Competition
0.00
0.00
Data
0.00
0.00
Reproducible
0.40
0.00
KG Connect
0.50
0.50
Score Breakdown
Dimension
SNCA Oligomers Sequester TFEB
GBA1 Loss Triggers a TFEB-to-T
Mechanistic
0.650
0.720
Evidence
0.720
0.650
Novelty
0.700
0.880
Feasibility
0.800
0.000
Impact
0.750
0.000
Druggability
0.000
0.000
Safety
0.000
0.000
Competition
0.000
0.000
Data
0.000
0.000
Reproducible
0.400
0.000
KG Connect
0.500
0.500
Evidence
SNCA Oligomers Sequester TFEB Phosphatases to Create a Phosp
No evidence citations yet
GBA1 Loss Triggers a TFEB-to-TFE3 Compensatory Switch in A9