🧪
hypothesis

C9orf72 repeat RNA and dipeptide-repeat toxicity in ALS/FTD

Hypothesis

C9orf72 repeat RNA and dipeptide-repeat toxicity in ALS/FTD

C9orf72 hexanucleotide repeat expansion produces repeat RNA foci and RAN-translated dipeptide-repeat proteins that disrupt nucleocytoplasmic transport, translation, stress granules, and neuronal survival.
🧬 C9orf72🩺 neurodegeneration🎯 Composite 70%💱 $0.59▼14.3%proposed
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 4 support✗ 2 oppose
✓ All Quality Gates Passed
Mechanistic 0.84 (15%) Evidence 0.82 (15%) Novelty 0.62 (12%) Feasibility 0.66 (12%) Impact 0.78 (12%) Druggability 0.74 (10%) Safety 0.56 (8%) Competition 0.50 (6%) Data Avail. 0.80 (5%) Reproducible 0.72 (5%) KG Connect 0.50 (8%) 0.700 composite
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Composite70%

🧪 Overview

C9orf72 hexanucleotide repeat expansion produces repeat RNA foci and RAN-translated dipeptide-repeat proteins that disrupt nucleocytoplasmic transport, translation, stress granules, and neuronal survival. The strongest program should not be DPR-only; it should separately interrogate sense RNA, antisense RNA, DPRs, and C9orf72 haploinsufficiency.

🧬 Mechanism

No curated mechanism pathway recorded for this hypothesis.

⚖️ Evidence

⚖️ Evidence Matrix4 supports2 contradicts
Supports
C9orf72 repeat expansion is the most common genetic cause of ALS/FTD.
PMID:21944778
Supports
Dipeptide-repeat proteins accumulate in patient neurons and are linked to pathology.
PMID:25437307
Supports
Poly-GR and poly-PR disrupt nuclear import in model systems.
PMID:26138283
Supports
Antisense oligonucleotide reduction of repeat products improves phenotypes in preclinical models.
PMID:25907378
Contradicts
DPR reduction alone may be insufficient, as BIIB078 reduced target biomarkers without clinical benefit.
PMID:NA
Contradicts
Persistent CNS pathologies after target engagement weaken a simple DPR-only therapeutic model.
PMID:40865525
📖 Linked Papers

No linked papers recorded for this hypothesis yet.

🏥 Translation

🧬 3D Protein Structure — C9ORF72

No curated PDB or AlphaFold mapping for C9ORF72 yet. Search RCSB →

💉 Clinical Trials

No clinical trials data linked to this hypothesis yet.

No curated ClinVar variants loaded for this hypothesis.

Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.

🔍 Search ClinVar for C9orf72 →

No DepMap CRISPR Chronos data found for C9orf72.

Run python3 scripts/backfill_hypothesis_depmap.py to populate.

🏆 Tournament

🏆 Arenas / Elo

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📊 Market Indicators

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💾 Resource Usage

No resource usage or linked notebooks recorded for this hypothesis yet.

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