Mechanistic description
Shared mechanism across ALS, FTD: Low-complexity RNA-binding proteins normally form reversible stress granules, but ALS/FTD-linked variants push granules toward persistent phase-separated assemblies that trap TDP-43 and impair RNA homeostasis. Different RBPs converge on the same granule-hardening mechanism.
Falsifiable prediction: Lowering TIA1 or hnRNPA1 granule persistence should shorten stress-granule half-life by at least 30% and reduce cytoplasmic TDP-43 recruitment in both ALS motor neurons and FTD cortical neurons carrying RBP/TDP-43 stress.
Proposed experiment: Introduce TIA1, HNRNPA1, or HNRNPA2B1 variants into isogenic motor and cortical neurons; apply ISR modulation or targeted RBP knockdown; image granule dynamics, FRAP recovery, TDP-43 recruitment, cryptic exon burden, and survival after stress.
Cross-disease confidence rationale: Direct TIA1 ALS/FTD evidence plus hnRNP prion-like domain ALS mechanism.
Internal SciDEX support: SciDEX support query found 41 matching hypotheses across 6 disease labels, including 41 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
- TIA1;HNRNPA1;HNRNPA2B1
- RNA-binding protein low-complexity domains, stress granules, and phase separation
- multi
Evidence for (3)
TIA1 mutations in ALS/FTD promote phase separation and alter stress granules.
hnRNPA2B1/hnRNPA1 prion-like domain mutations cause multisystem proteinopathy and ALS.
TDP-43 pathology provides a shared ALS/FTD downstream anchor.
Evidence against (1)
Evidence matrix
Supporting
- TIA1 mutations in ALS/FTD promote phase separation and alter stress granules. PMID:28817800 · 2017 · 10.1016/j.neuron.2017.07.025
- hnRNPA2B1/hnRNPA1 prion-like domain mutations cause multisystem proteinopathy and ALS. PMID:23455423 · 2013 · 10.1038/nature11922
- TDP-43 pathology provides a shared ALS/FTD downstream anchor. PMID:17023659 · 2006 · 10.1126/science.1134108
Contradicting
No contradicting evidence recorded.
Top-ranked evidence
trust_score × relevance_score × exp(-recency_weight × recency_days / 365)
Supports · top 3
- #1 paper-8d62880a6e04 0.471
- #2 e89295a9-5ca0-4db3-85e2-2257d7f6caf8 0.471
- #3 ca8fac23-ffac-401f-8b8a-8f6e755ec6ef 0.235
Cite this hypothesis
Cite this hypothesis
etl-backfill (2026). Stress-granule RNA-binding protein phase transition across ALS and FTD. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-cross-synth-stress-granule-rbps
@misc{scidex_hypothesis_hcrosssy,
title = {Stress-granule RNA-binding protein phase transition across ALS and FTD},
author = {etl-backfill},
year = {2026},
howpublished = {SciDEX hypothesis},
url = {https://prism.scidex.ai/hypotheses/h-cross-synth-stress-granule-rbps},
note = {SciDEX artifact hypothesis:h-cross-synth-stress-granule-rbps}
}