All challenges
- Resolve: VCP/p97 ATPase mutations impair extraction of ubiquitinated autophagy substrates
Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=VCP). Hypothesis: Do VCP/p97 mutations (common in IBMPFD/ALS) impair extraction of ubiquitinated autophagy substrates, causing proteasome-autophagy f…
- Resolve: NLRP3 Inflammasome Lock Perpetuates Senescence-Associated Inflammasome Phenotype
Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=NLRP3/CASP1/IL1B). Hypothesis: Does the NLRP3 inflammasome enter a locked 'hyperactive' state in senescent astrocytes that perpetuates the senescence…
- Resolve: C9orf72 ASO Treatment Reverses TDP-43 Pathology in ALS/FTD
Falsifiable prediction from high-scoring hypothesis (score=0.720, gene=C9orf72). Hypothesis: Does antisense oligonucleotide (ASO) targeting C9orf72 repeat expansions reduce TDP-43 mislocalization and restore motor functi…
- Resolve: LXRβ-Selective Agonism as a Precision Therapeutic for APOE4-Driven Myelin Deficits
Falsifiable prediction from high-scoring hypothesis (score=0.721, gene=NR1H2 (LXRβ)). Hypothesis: Does APOE4-driven impairment of oligodendrocyte cholesterol efflux via reduced LXRβ signaling cause myelin instability, an…
- Resolve: Cortico-Striatal Synchrony Restoration via NMDA Modulation
Falsifiable prediction from high-scoring hypothesis (score=0.723, gene=GRIN2B). Hypothesis: Does enhancing GluN2B-containing NMDA receptor activity at cortico-striatal synapses restore 30-40 Hz beta-band synchrony and im…
- Resolve: TDP-43 condensation thermodynamics as a therapeutic target and biomarker for nuclear-cytoplasmic compartmentalization
Falsifiable prediction from high-scoring hypothesis (score=0.724, gene=TARDBP). Hypothesis: Does TDP-43 liquid-liquid phase separation (LLPS) state — measured by FRAP — predict therapeutic response to nuclear import rece…
- Resolve: Calcium-Dependent S100B Release from Astrocyte End-Feet as an Early Signal of Astrocyte-Mediated BBB Dysfunction
Falsifiable prediction from high-scoring hypothesis (score=0.725, gene=S100B). Hypothesis: Can serum S100B serve as an early biomarker of BBB dysfunction in AD, preceding amyloid/tau pathology by >3 years, and does block…
- Resolve: Microglial TREM2-Complement Axis Modulation
Falsifiable prediction from high-scoring hypothesis (score=0.726, gene=TREM2 and C3). Hypothesis: Can selective modulation of the TREM2-C3 axis (TREM2 agonism + C3 inhibition) simultaneously restore microglial phagocytos…
- Resolve: TFEB/TFE3 Parallel Activation Drives Coordinated Organelle Clearance via CLEAR Network
Falsifiable prediction from high-scoring hypothesis (score=0.727, gene=TFEB (TFEB), TFE3 (TFE3)). Hypothesis: Does parallel activation of TFEB and TFE3 synergistically enhance lysosomal and mitochondrial biogenesis throu…
- Resolve: Selective LXRβ agonists restore ABCA1/ABCG1 expression and APOE lipidation in APOE4 astrocytes
Falsifiable prediction from high-scoring hypothesis (score=0.728, gene=NR1H2 (LXRβ), ABCA1, ABCG1). Hypothesis: Can selective LXRβ agonism restore cholesterol efflux in APOE4 astrocytes by upregulating ABCA1/ABCG1, norma…
- Resolve: SCFA Deficiency Drives Microglial Hyperactivation via GPR43/NF-κB Dysregulation
Falsifiable prediction from high-scoring hypothesis (score=0.728, gene=GPR43 (FFAR2)). Hypothesis: Does restoring gut-microbiome-derived SCFA (butyrate/propionate) levels rescue microglial GPR43-mediated HDAC inhibition…
- Resolve: p21^Cip1 Phospho-State as Autophagy Responsiveness Predictor
Falsifiable prediction from high-scoring hypothesis (score=0.729, gene=CDKN1A). Hypothesis: Does distinct phosphorylation state of p21^Cip1 predict cellular responsiveness to autophagy-inducing therapies, enabling precis…
- Resolve: Cav3.2 T-Type Calcium Channel–Driven Calcium Overload Triggers Calpain-PP2A Cascade and Proteostasis Collapse in Entorhinal Layer II Neurons
Layer II stellate neurons of the entorhinal cortex are among the earliest and most selectively vulnerable in Alzheimer's disease. Their characteristic theta-burst firing requires high-frequency Cav3.2 (T-type) channel ac…
- Resolve: Endosomal Trafficking Defects (SORL1/BIN1/PICALM) Are the Common Upstream Lesion for Both APP Amyloidogenesis and Cholinergic Trophic Failure
Genome-wide significant AD risk loci including SORL1, BIN1, PICALM, and VPS35 converge on endosomal trafficking pathways, but their mechanistic outputs are typically studied in isolation. This hypothesis proposes a unify…
- Resolve: G2019S LRRK2 Creates Pathogenic Positive Feedback as Lysosomal Volume-Sensing Amplifier via RAB29
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 th…
- Resolve: AD Biomarker Trajectory Is Subtype-Stratified, Not Universal — APOE/SORL1 vs NTRK1/BIN1
Current AD staging frameworks (A/T/N) assume a universal amyloid-first cascade, but clinical heterogeneity in biomarker ordering suggests AD comprises mechanistically distinct subtypes. This hypothesis proposes that SORL…
- Resolve: Astrocyte Metabolic-Secretome Failure Drives RBP Mislocalization via Lactate Shuttle Collapse
The astrocyte-neuron lactate shuttle (ANLS) is a fundamental metabolic support axis; astrocytes export lactate via MCT4, neurons import via MCT2, and neuronal ATP generated from lactate drives chaperone activity that mai…
- Resolve: Ubiquitin-K63 Chains Drive Liquid-to-Solid Stress Granule Transition via G3BP1 Crowding in ALS/FTD
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 nuc…
- Resolve: Selective nSMase2 (SMPD3) Inhibition Blocks Ceramide-Driven Neurodegeneration Without Lysosomal Liabilities
Neutral sphingomyelinase-2 (nSMase2, encoded by SMPD3) operates at the plasma membrane and generates ceramide in response to inflammatory cytokines, oxidative stress, and glutamate excitotoxicity—all relevant to neurodeg…
- Resolve: SMPD1 Inhibition Reduces Ceramide-Driven BACE1 Upregulation and Aβ Production in AD
Dysregulated sphingolipid metabolism is a convergent feature of Alzheimer's disease, with acid sphingomyelinase (ASMase/SMPD1) overactivity driving ceramide accumulation in neuronal membrane microdomains. Elevated cerami…
- 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 mech…
- Resolve: Seed-Proximal Asymmetric Duplex Stability Governs lncRNA-0021/miR-6361 Selectivity
lncRNA-0021/miR-6361 specificity is proposed to arise from asymmetric duplex stability rather than sequence uniqueness: a G:C-enriched proximal half-seed enables thermodynamically distinct 'zipper' kinetics that block mi…
- Resolve: microglial IGFBPL1 AAV delivery improves neuroinflammatory phenotype
Bounty tier: $250K delivery feasibility. This challenge tests both CNS delivery and microglial cell-state effect, the two largest uncertainties in the drug-delivery hypothesis. Falsifiable prediction: AAV-PHP.eB-CX3CR1-I…
- Resolve: TBK1-autophagy receptor failure traps G3BP1 stress granules
Bounty tier: $500K ALS autophagy validation. The challenge distinguishes defective receptor recruitment from generic stress-granule overproduction. Falsifiable prediction: TBK1 loss-of-function or kinase inhibition in iP…
- Resolve: C9orf72 DPR blockade of nucleocytoplasmic transport
Bounty tier: $500K cellular mechanism. The challenge asks whether C9orf72 DPR species are sufficient and necessary to cause an early NUP98/RanGAP1 transport defect. Falsifiable prediction: inducible poly-GR or poly-PR ex…