C9ORF72 autophagy-lysosome collapse across ALS and FTD

Mechanistic description

Shared mechanism across ALS, FTD: C9ORF72 repeat expansion creates toxic RNA/dipeptide stress while also weakening vesicle trafficking, autophagy, and basal mitophagy. The same upstream repeat biology can manifest as motor-neuron ALS, cortical FTD, or mixed ALS-FTD depending on cell-type stress thresholds.

Falsifiable prediction: Correcting C9ORF72 repeat RNA with ASO should restore basal mitophagy flux by at least 20% and reduce p62-positive autophagy backlog in both motor neurons and frontotemporal cortical neurons from the same carrier lines.

Proposed experiment: Generate paired motor neuron and cortical neuron cultures from C9ORF72 carriers; apply repeat-targeting ASO; measure RNA foci, DPR proteins, LC3/p62 flux, basal mitophagy reporters, TDP-43 mislocalization, and cell-type survival.

Cross-disease confidence rationale: Two independent discovery papers identify the ALS-FTD repeat, with newer mitophagy evidence.

Internal SciDEX support: SciDEX support query found 55 matching hypotheses across 5 disease labels, including 55 with debate_count > 0.

Generated by task ffd81f3a-7f04-4db1-8547-1778ce030e89 as a cross-disease mechanism synthesis, not a single-disease hypothesis renamed as multi-disease.

Mechanism / pathway

C9ORF72
→
C9ORF72 repeat toxicity, basal mitophagy, and autophagy-lysosome trafficking
→
multi

Evidence for (3)

C9ORF72 GGGGCC repeat expansion causes chromosome 9p-linked FTD and ALS.

PMID:21944778 2011
C9ORF72 repeat expansion is the cause of chromosome 9p21-linked ALS-FTD.

PMID:21944779 2011
C9ORF72 repeat expansion produces toxic RNA foci that directly disrupt autophagic flux by sequestering essential RNA-binding proteins required for autophagosome-lysosome fusion.

PMID:27112499

Evidence against (1)

PMID:33632058 2021

Evidence matrix

3 supporting 0 contradicting

100% supporting

Supporting

C9ORF72 GGGGCC repeat expansion causes chromosome 9p-linked FTD and ALS. PMID:21944778 · 2011 · 10.1016/j.neuron.2011.09.011
C9ORF72 repeat expansion is the cause of chromosome 9p21-linked ALS-FTD. PMID:21944779 · 2011 · 10.1016/j.neuron.2011.09.010
C9ORF72 repeat expansion produces toxic RNA foci that directly disrupt autophagic flux by sequestering essential RNA-binding proteins required for autophagosome-lysosome fusion. PMID:27112499

Contradicting

No contradicting evidence recorded.

Top-ranked evidence

trust_score × relevance_score × exp(-recency_weight × recency_days / 365)

Supports · top 2

#1 paper-c5d050a212ca 0.467 trust 0.50 · rel 1.00 · 82d
#2 1c5afdb9-c6a8-44d0-9382-154cf18f1a62 0.467 trust 0.50 · rel 1.00 · 82d

2 total ranked · scidex.hypotheses.evidence_ranking

Cite this hypothesis

Citation

etl-backfill (2026). C9ORF72 autophagy-lysosome collapse across ALS and FTD. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-cross-synth-c9orf72-autophagy-lysosome

BibTeX

@misc{scidex_hypothesis_hcrosssy,
  title        = {C9ORF72 autophagy-lysosome collapse across ALS and FTD},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-cross-synth-c9orf72-autophagy-lysosome},
  note         = {SciDEX artifact hypothesis:h-cross-synth-c9orf72-autophagy-lysosome}
}