Version history

{
  "description": "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.",
  "challenge_type": "open",
  "scope": "hypothesis",
  "initial_bounty_usd": 500000,
  "current_bounty_usd": 500000,
  "bounty_confidence": 0.63,
  "market_price": 0.5,
  "composite_score": 0.733,
  "debate_count": 0,
  "status": "open",
  "question": "Do SNCA oligomers physically occlude the torsinA-LAMP2A interaction interface (LAMP2A cytosolic residues 1-24), preventing LAMP2A membrane extraction and thereby locking chaperone-mediated autophagy in a hyperstabilized, substrate-overloaded state?",
  "domain": "neurodegeneration",
  "triggered_by": "hypothesis:hyp-lyso-snca-548064db6357"
}