From Analysis:
Gap 006 analysis (archived stub)
Analysis for knowledge gap 006 in the neurodegeneration domain.
Molecular Mechanism and Rationale
The pathogenesis of frontotemporal dementia with GRN mutations (FTD-GRN) involves a complex interplay between progranulin haploinsufficiency and disrupted astrocyte-neuron metabolic coupling. Progranulin (PGRN), encoded by the GRN gene, is a secreted glycoprotein that plays crucial roles in neuroinflammation, lysosomal function, and cellular metabolism. In FTD-GRN, heterozygous loss-of-function mutations result in ~50% reduction in progranulin levels, triggering a cascade of metabolic dysfunction that precedes overt neurodegeneration.
No AI visual card yet
Curated pathway diagram from expert analysis
flowchart TD
A["SLC16A3/MCT4
Monocarboxylate Transporter 4"]
B["Lactate Export
Warburg Effect Adaptation"]
C["Astrocyte Lactate Shuttle
Neuronal Energy Support"]
D["Neuronal Metabolism
Pyruvate and Lactate Uptake"]
E["LDHA Activation
Pyruvate to Lactate Conversion"]
F["Glycolytic Shift
Mitochondrial Function Reduced"]
G["Astrocyte-Neuron Coupling
Metabolic Interaction Failure"]
H["Synaptic Failure
Energy Deficit at Synapses"]
I["Neurodegeneration
Metabolic Collapse"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
G --> H
H --> I
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style I fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
Median TPM across 13 brain regions for GRN, SLC16A3 (MCT4) from GTEx v10.
Mechanism: TDP-43 proteinopathy leads to progressive nuclear depletion of functional TDP-43, causing widespread alternative splicing defects at synapses, part
Temporal Causality Assumption
The hypothesis assumes nuclear TDP-43 depletion drives splicing dysfunction rather than being a consequence of earlier upstream insults. This assumes causation from correlation—a foundational logical flaw. Nuclear depletion may be a compensatory response, an epiphenomenon, or a parallel process occurring alongside (not before) other pathogenic events.
Specificity Problem
TDP-43 regulates thousands of sp
| Hypothesis | Primary Modality | Feasibility Tier | Timeline | Cost Range |
|------------|------------------|------------------|----------|------------|
| 7. cGAS-STING/Tau | STING inhibitors | Tier 1 | 5-8 yr | $100-200M |
| 2. TREM2/DAM | Agonist antibodies | Tier 2 | 6-9 yr | $150-250M |
| 6. Astrocyte/GRN | MCT4 modulators | Tier 2 | 7-10 yr | $150-250M |
| 1. TDP-43/Splicing | ASOs | Tier 3 | 10-12 yr | $150-300M |
| 3. Lysosome/αSyn | TRPML1 agonists | Tier 3
{
"ranked_hypotheses": [
{
"title": "cGAS-STING Pathway Hyperactivation Mediates Tau Propagation",
"description": "Pathological tau triggers cytosolic DNA release and mitochondrial DNA stress, activating cGAS-STING signaling in neurons and microglia. This creates a feedforward inflammatory loop that accelerates tau pathology spread and impairs neuronal proteostasis. Tier 1 translational feasibility with 5-8 year development timeline.",
"target_gene": "cGAS (CGAS), STING (TMEM173)",
"dimension_scores": {
"evidence_strength": 0.76,
"novelty": 0.70,
No clinical trials data available
Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
No citation freshness data yet. Export bibliography — run scripts/audit_citation_freshness.py to populate.
Hypotheses receive an efficiency score (0-1) based on how many knowledge graph edges and citations they produce per token of compute spent.
High-efficiency hypotheses (score >= 0.8) get a price premium in the market, pulling their price toward $0.580.
Low-efficiency hypotheses (score < 0.6) receive a discount, pulling their price toward $0.420.
Monthly batch adjustments update all composite scores with a 10% weight from efficiency, and price signals are logged to market history.
Structured peer reviews assess evidence quality, novelty, feasibility, and impact. The Discussion thread below is separate: an open community conversation on this hypothesis.
No DepMap CRISPR Chronos data found for GRN, SLC16A3 (MCT4).
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No governance decisions recorded for this hypothesis.
Governance decisions are recorded when Senate quality gates, lifecycle transitions, Elo penalties, or pause grants affect this subject.
Molecular pathway showing key causal relationships underlying this hypothesis
graph TD
sess_SDA_2026_04_02_gap_2["sess_SDA-2026-04-02-gap-2026-04-01-gap-006_task_9aae8fc5"] -->|produced| SDA_2026_04_02_gap_2026_0["SDA-2026-04-02-gap-2026-04-01-gap-006"]
Reduced_MCT4_expression["Reduced MCT4 expression"] -.->|reduces| astrocyte_lactate_product["astrocyte lactate production"]
Reduced_lactate_productio["Reduced lactate production"] -.->|reduces| neuronal_glucose_uptake["neuronal glucose uptake"]
Type_I_interferon_respons["Type I interferon response"] -->|correlates with| AD_and_Pick_s_disease["AD and Pick's disease"]
TREM2_loss_of_function["TREM2 loss-of-function"] -->|impairs| DAM_transition["DAM transition"]
TREM2_deficiency["TREM2 deficiency"] -->|prevents| amyloid_plaque_phagocytos["amyloid plaque phagocytosis"]
Trem2_knockout["Trem2 knockout"] -->|increases| amyloid_seeding["amyloid seeding"]
TREM2_agonist_antibodies["TREM2-agonist antibodies"] -->|promotes| microglial_amyloid_uptake["microglial amyloid uptake"]
Progranulin_haploinsuffic["Progranulin haploinsufficiency"] -->|impairs| astrocyte_lactate_product_1["astrocyte lactate production"]
Progranulin_haploinsuffic_2["Progranulin haploinsufficiency"] -->|causes| FTD["FTD"]
cGAS_STING["cGAS-STING"] -->|activates| neuroinflammation["neuroinflammation"]
cGAS_STING_3["cGAS-STING"] -->|impairs| neuronal_proteostasis["neuronal proteostasis"]
style sess_SDA_2026_04_02_gap_2 fill:#4fc3f7,stroke:#333,color:#000
style SDA_2026_04_02_gap_2026_0 fill:#4fc3f7,stroke:#333,color:#000
style Reduced_MCT4_expression fill:#4fc3f7,stroke:#333,color:#000
style astrocyte_lactate_product fill:#4fc3f7,stroke:#333,color:#000
style Reduced_lactate_productio fill:#4fc3f7,stroke:#333,color:#000
style neuronal_glucose_uptake fill:#4fc3f7,stroke:#333,color:#000
style Type_I_interferon_respons fill:#81c784,stroke:#333,color:#000
style AD_and_Pick_s_disease fill:#ef5350,stroke:#333,color:#000
style TREM2_loss_of_function fill:#ce93d8,stroke:#333,color:#000
style DAM_transition fill:#4fc3f7,stroke:#333,color:#000
style TREM2_deficiency fill:#ce93d8,stroke:#333,color:#000
style amyloid_plaque_phagocytos fill:#4fc3f7,stroke:#333,color:#000
style Trem2_knockout fill:#ce93d8,stroke:#333,color:#000
style amyloid_seeding fill:#4fc3f7,stroke:#333,color:#000
style TREM2_agonist_antibodies fill:#4fc3f7,stroke:#333,color:#000
style microglial_amyloid_uptake fill:#4fc3f7,stroke:#333,color:#000
style Progranulin_haploinsuffic fill:#ce93d8,stroke:#333,color:#000
style astrocyte_lactate_product_1 fill:#4fc3f7,stroke:#333,color:#000
style Progranulin_haploinsuffic_2 fill:#ce93d8,stroke:#333,color:#000
style FTD fill:#ef5350,stroke:#333,color:#000
style cGAS_STING fill:#81c784,stroke:#333,color:#000
style neuroinflammation fill:#4fc3f7,stroke:#333,color:#000
style cGAS_STING_3 fill:#81c784,stroke:#333,color:#000
style neuronal_proteostasis fill:#4fc3f7,stroke:#333,color:#000
neurodegeneration | 2026-04-02 | archived
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