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
Radar Chart — 10 Dimensions
Score Comparison Bars
Mechanistic
0.72
Evidence
0.65
Novelty
0.88
Feasibility
0.00
Impact
0.00
Druggability
0.00
Safety
0.00
Competition
0.00
Data
0.00
Reproducible
0.00
KG Connect
0.54
Score Breakdown
Dimension
GBA1 Loss Triggers a TFEB-to-T
Mechanistic
0.720
Evidence
0.650
Novelty
0.880
Feasibility
0.000
Impact
0.000
Druggability
0.000
Safety
0.000
Competition
0.000
Data
0.000
Reproducible
0.000
KG Connect
0.540
Evidence
GBA1 Loss Triggers a TFEB-to-TFE3 Compensatory Switch in A9