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

Mechanistic description

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 / pathway

C9orf72
→
neurodegeneration

Evidence for (4)

C9orf72 repeat expansion is the most common genetic cause of ALS/FTD.

PMID:21944778
Dipeptide-repeat proteins accumulate in patient neurons and are linked to pathology.

PMID:25437307
Poly-GR and poly-PR disrupt nuclear import in model systems.

PMID:26138283
Antisense oligonucleotide reduction of repeat products improves phenotypes in preclinical models.

PMID:25907378

Evidence against (2)

DPR reduction alone may be insufficient, as BIIB078 reduced target biomarkers without clinical benefit.

PMID:NA
Persistent CNS pathologies after target engagement weaken a simple DPR-only therapeutic model.

PMID:40865525

Evidence matrix

4 supporting 2 contradicting

67% supporting

Supporting

C9orf72 repeat expansion is the most common genetic cause of ALS/FTD. PMID:21944778
Dipeptide-repeat proteins accumulate in patient neurons and are linked to pathology. PMID:25437307
Poly-GR and poly-PR disrupt nuclear import in model systems. PMID:26138283
Antisense oligonucleotide reduction of repeat products improves phenotypes in preclinical models. PMID:25907378

Contradicting

DPR reduction alone may be insufficient, as BIIB078 reduced target biomarkers without clinical benefit. PMID:NA
Persistent CNS pathologies after target engagement weaken a simple DPR-only therapeutic model. PMID:40865525

Cite this hypothesis

Citation

etl-backfill (2026). C9orf72 repeat RNA and dipeptide-repeat toxicity in ALS/FTD. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-fb25a50427

BibTeX

@misc{scidex_hypothesis_hfb25a50,
  title        = {C9orf72 repeat RNA and dipeptide-repeat toxicity in ALS/FTD},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-fb25a50427},
  note         = {SciDEX artifact hypothesis:h-fb25a50427}
}