Version history

{
  "description": "LRRK2-G2019S is the most common genetic cause of familial Parkinson's disease, but why G2019S kinase hyperactivation is more pathogenic than proportional kinase overexpression remains unclear. This hypothesis proposes that G2019S specifically amplifies the volume-sensing positive feedback loop: when lysosomes swell (e.g., due to substrate overload), RAB29 recruits LRRK2 to the trans-Golgi network, which phosphorylates RAB10 to amplify LRRK2 membrane residence and kinase output. G2019S exaggerates the slope of this response, creating runaway positive feedback under mild lysosomal stress that WT LRRK2 would self-limit. The challenge requires: (1) real-time lysosomal volume monitoring (LysoTracker + osmotic swelling) with kinetic LRRK2/RAB29 recruitment and phospho-RAB10 measurement by quantitative IF; (2) comparison of response slope (dpRAB10/dt) between G2019S and WT under identical swelling; (3) LRRK2 kinase-dead rescue to distinguish amplification from baseline elevation; (4) RAB29 knockout to confirm recruitment-dependence. Falsifiable prediction: G2019S should show ≥2× faster phospho-RAB10 rise rate (slope, not peak) than WT under hypo-osmotic lysosomal stress; RAB29 KO should flatten this differential to ≤1.2×. Bounty tier: $500K LRRK2/lysosomal signaling kinetics in PD.",
  "challenge_type": "open",
  "scope": "hypothesis",
  "initial_bounty_usd": 500000,
  "current_bounty_usd": 500000,
  "bounty_confidence": 0.64,
  "market_price": 0.5,
  "composite_score": 0.73,
  "debate_count": 0,
  "status": "open",
  "question": "Does LRRK2-G2019S exhibit disproportionately amplified RAB10 phosphorylation kinetics (slope, not baseline) in response to lysosomal swelling signals via RAB29, compared to wild-type LRRK2, and does this amplified feedback loop drive lysosomal dysfunction independent of baseline LRRK2 kinase overactivation?",
  "domain": "neurodegeneration",
  "triggered_by": "hypothesis:h-a0269f3c81"
}