Version history

{
  "description": "ALS/FTD-linked RNA-binding proteins including TDP-43 undergo liquid-to-solid phase transitions within stress granules that are pathologically relevant but mechanistically underexplored. G3BP1 is a core stress granule nucleator that regulates condensate material properties. K63-linked ubiquitylation of G3BP1 during chronic stress is proposed to increase intermolecular bridging and reduce condensate fluidity, effectively 'locking' stress granules and sequestering RBPs. Disrupting K63-chain formation or bridging offers a therapeutic strategy distinct from solubilizing aggregates already formed. The challenge requires: (1) mass-spec identification of G3BP1 ubiquitylation sites under chronic arsenite stress; (2) K63-specific deubiquitylase (AMSH-LP) treatment and fluorescence recovery after photobleaching to measure condensate fluidity; (3) TDP-43 nuclear vs. cytoplasmic distribution rescue by K63-chain competition; (4) iPSC-motor neuron validation. Falsifiable prediction: K63-chain competition (using K63-UIM decoy) should restore condensate fluidity (FRAP t1/2 ≤5× control) in ≥70% of cells and reduce cytoplasmic TDP-43 fraction by ≥40% in ALS iPSC-motor neurons under chronic stress. Bounty tier: $500K condensate biology / ALS-FTD mechanistic study.",
  "challenge_type": "open",
  "scope": "hypothesis",
  "initial_bounty_usd": 500000,
  "current_bounty_usd": 500000,
  "bounty_confidence": 0.62,
  "market_price": 0.5,
  "composite_score": 0.73,
  "debate_count": 0,
  "status": "open",
  "question": "Do K63-linked ubiquitin chains accumulate on G3BP1 during chronic stress to increase stress granule viscosity and block dissolution, and does deubiquitylation or competition with K63-chain binding re-liquify pathological granules and reduce TDP-43 cytoplasmic sequestration?",
  "domain": "neurodegeneration",
  "triggered_by": "hypothesis:h-9c5abf9343"
}