Resolve: SNCA Oligomers Block TorsinA-Mediated LAMP2A Turnover, Stabilizing CMA Dysfunction in PD

Chaperone-mediated autophagy (CMA) failure in Parkinson's disease is well-established, but the molecular mechanism by which SNCA oligomers impair LAMP2A recycling remains debated. This hypothesis proposes a specific mechanistic step: SNCA oligomers compete with torsinA for the LAMP2A cytosolic tail, preventing AAA+ ATPase-mediated extraction of aged LAMP2A from the lysosomal membrane. The stabilized LAMP2A pool becomes saturated with substrate but cannot turnover, creating a dysfunctional substrate-queue that drives SNCA accumulation. The challenge requires: (1) co-IP between torsinA and LAMP2A cytosolic tail peptide ± SNCA oligomers to quantify competitive binding; (2) pulse-chase LAMP2A turnover kinetics in SH-SY5Y cells expressing oligomer-biased SNCA-E46K vs. monomer-biased SNCA-A53T; (3) lysosomal membrane fractionation to confirm LAMP2A hyperstabilization. Falsifiable prediction: SNCA oligomers at 5:1 molar ratio to LAMP2A cytosolic tail should reduce torsinA binding by ≥50% in pulldown assay; LAMP2A half-life should extend ≥2-fold in E46K-expressing neurons vs. monomer-control. Bounty tier: $500K mechanistic PD lysosomal biology study with direct therapeutic implications for CMA enhancement strategies.

$500.0K
OPEN
Confidence:
63%
Created: 2026-04-28

Linked Targets (1)

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

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Detected Targets:
SNCA

3D Protein Structure

View 3D structure: SNCA — PDB 1XQ8

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

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Linked Hypotheses (1)

SNCA Oligomer Binding to LAMP2A Cytosolic Tail Prevents TorsinA-Mediated LAMP2A LAMP20.73