TDP-43 LLPS and proteostasis dysregulation in ALS/FTD

Mechanistic description

TDP-43 stress-granule entry and liquid-liquid phase separation may transition from reversible condensates into pathological aggregates when chaperone disassembly and post-translational regulation fail. The therapeutic opportunity is biologically compelling but not yet product-shaped; success requires restoring nuclear TDP-43 function and RNA-splicing integrity, not only dissolving inclusions.

Mechanism / pathway

TARDBP
→
neurodegeneration

Evidence for (4)

TDP-43 forms stress granules through LLPS under physiological stress conditions.

PMID:24670997
Pathological TDP-43 aggregates colocalize with stress-granule markers in ALS tissue.

PMID:28661562
TARDBP mutations cause familial ALS, confirming disease relevance.

PMID:19479373
TDP-43 frameshift mutations alter LLPS behavior.

PMID:31853077

Evidence against (2)

LLPS-to-aggregation is plausible but not therapeutically settled, and inclusions may be downstream of broader nuclear loss-of-function and proteostasis failure.

PMID:38029395
Stress-granule colocalization does not prove stress granules seed disease in vivo.

PMID:NA

Evidence matrix

4 supporting 2 contradicting

67% supporting

Supporting

TDP-43 forms stress granules through LLPS under physiological stress conditions. PMID:24670997
Pathological TDP-43 aggregates colocalize with stress-granule markers in ALS tissue. PMID:28661562
TARDBP mutations cause familial ALS, confirming disease relevance. PMID:19479373
TDP-43 frameshift mutations alter LLPS behavior. PMID:31853077

Contradicting

LLPS-to-aggregation is plausible but not therapeutically settled, and inclusions may be downstream of broader nuclear loss-of-function and proteostasis failure. PMID:38029395
Stress-granule colocalization does not prove stress granules seed disease in vivo. PMID:NA

Cite this hypothesis

Citation

etl-backfill (2026). TDP-43 LLPS and proteostasis dysregulation in ALS/FTD. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-30afe4733d

BibTeX

@misc{scidex_hypothesis_h30afe47,
  title        = {TDP-43 LLPS and proteostasis dysregulation in ALS/FTD},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-30afe4733d},
  note         = {SciDEX artifact hypothesis:h-30afe4733d}
}