➡ Upstream Target
Parkinson's diseaseDruggability: 0.75
MECHANISM
Lysosomal glucocerebrosidase deficiency → impaired autophagosome-lysosome fusion → α-synuclein clearance failure → mitochondrial dysfunction → neuroinflammation → DA neuron loss
✗ KILL CRITERIA
- GCase activity restoration fails to reduce SNCA aggregation in patient iPSC DA neurons
- Lysosomal flux improvement does not reduce α-synuclein in GBA1-PD models
- GCase chaperone (ambroxol) fails to slow progression in Phase 3 RCT