Resolve: Lysosomal Acidification Failure via GBA1/LAMP2A Autophagy Convergence

Lysosomal acidification is critical for both chaperone-mediated autophagy (CMA via LAMP2A) and glucocerebrosidase activity (GCase/GBA1). The convergence hypothesis proposes that simultaneous dysfunction of both pathways creates a catastrophic failure of lysosomal proteostasis. This challenge seeks to establish: (1) whether the two deficits are truly synergistic (not merely additive), (2) the molecular mechanism linking them, and (3) whether restoring lysosomal pH via acidifying agents (or TFEB activation) can rescue both. Falsifiable prediction: dual knockdown of GBA1 and LAMP2A in dopaminergic neurons should increase SNCA aggregate burden by >2× versus single knockdowns combined, rescued by acidifying nanoparticles.

$500
OPEN
Confidence:
63%
Created: 2026-04-28

Linked Targets (2)

TFEB TFEB Protein PDB:5HQB0.34
🧬 View 3D Structure — PDB 5HQB click to expand

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SNCA Synuclein alpha PDB:1XQ80.60
🧬 View 3D Structure — PDB 1XQ8 click to expand

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Detected Targets:
GBA1TFEBSNCA

3D Protein Structure

View 3D structure: GBA1 — PDB 2V3D

Experimental structure from RCSB PDB | Powered by Mol* | Rotate: click+drag | Zoom: scroll

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Linked Hypotheses (1)

Lysosomal Acidification Failure: Convergent GBA1/LAMP2A–mediated Autophagy Dysfu GBA1,LAMP2A,SCARB2,CTSB,CTSD,T0.70