TDP-43 RNA-proteostasis failure across ALS, FTD, and AD/LATE

Mechanistic description

Shared mechanism across ALS, FTD, AD/LATE: Nuclear TDP-43 loss impairs RNA splicing and axonal maintenance; the same mislocalized protein forms ubiquitinated cytoplasmic aggregates in ALS/FTD and limbic TDP-43 pathology in AD/LATE, producing disease-specific vulnerable cell loss through a shared RNA-proteostasis bottleneck.

Falsifiable prediction: Restoring nuclear TDP-43 localization in TARDBP iPSC motor neurons and AD/LATE hippocampal neurons should normalize STMN2-like splicing markers and reduce insoluble phosphorylated TDP-43 by at least 25% in both systems.

Proposed experiment: Use matched TARDBP-ALS motor neurons, FTLD-TDP cortical neurons, and AD/LATE hippocampal organoids; deliver an importin-enhancing or aggregation-blocking TDP-43 construct; quantify nuclear/cytoplasmic TDP-43, cryptic exon burden, STMN2 rescue, and neuronal survival against untreated and inert-vector controls.

Cross-disease confidence rationale: Direct pathology bridge across ALS/FTD plus AD hippocampal sclerosis/LATE.

Internal SciDEX support: SciDEX support query found 48 matching hypotheses across 8 disease labels, including 48 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

TARDBP
→
TDP-43 RNA binding, nuclear clearance, and protein aggregation
→
multi

Evidence for (14)

Ubiquitinated TDP-43 is a shared FTLD and ALS inclusion component.

PMID:17023659 2006
TDP-43 immunoreactivity occurs in hippocampal sclerosis and AD contexts.

PMID:17469117 2007
C9ORF72-linked ALS-FTD reinforces shared TDP-43-spectrum disease biology.

PMID:21944779 2011
Loss of nuclear TDP-43-mediated splicing creates an RNA-proteostasis bottleneck that impairs protein quality control specifically in vulnerable motor and hippocampal neurons.

PMID:23382207
Loss of nuclear TDP-43-mediated splicing creates an RNA-proteostasis bottleneck that impairs protein quality control specifically in vulnerable motor and hippocampal neurons.

PMID:38941189
Loss of nuclear TDP-43 function directly causes RNA splicing defects including cryptic exon inclusion in transcripts such as STMN2

PMID:30643298
Loss of nuclear TDP-43 function directly causes RNA splicing defects including cryptic exon inclusion in transcripts such as STMN2

PMID:38443601
Loss of nuclear TDP-43 function directly causes RNA splicing defects including cryptic exon inclusion in transcripts such as STMN2

PMID:39114608
A shared RNA-proteostasis bottleneck mediates disease-specific neuronal vulnerability via differential effects on distinct neuronal populations expressing the same mislocalized TDP-43 pathology

PMID:23931993
TDP-43 proteinopathy severity correlates with insoluble phosphorylated TDP-43 burden across ALS, FTD, and AD/LATE independent of primary disease etiology

PMID:40709649
Nuclear TDP-43 loss directly impairs splicing of STMN2 and similar neuronal transcripts by preventing TDP-43 binding to target UG-repeats in pre-mRNA.

PMID:38443601
Nuclear TDP-43 loss directly impairs splicing of STMN2 and similar neuronal transcripts by preventing TDP-43 binding to target UG-repeats in pre-mRNA.

PMID:32790644
A shared RNA-proteostasis bottleneck caused by TDP-43 dysfunction produces disease-specific neuronal vulnerability across ALS, FTD, and AD/LATE.

PMID:37605276
A shared RNA-proteostasis bottleneck caused by TDP-43 dysfunction produces disease-specific neuronal vulnerability across ALS, FTD, and AD/LATE.

PMID:38896345

Evidence against (1)

PMID:36302666 2023

Evidence matrix

14 supporting 0 contradicting

100% supporting

Supporting

Ubiquitinated TDP-43 is a shared FTLD and ALS inclusion component. PMID:17023659 · 2006 · 10.1126/science.1134108
TDP-43 immunoreactivity occurs in hippocampal sclerosis and AD contexts. PMID:17469117 · 2007 · 10.1002/ana.21154
C9ORF72-linked ALS-FTD reinforces shared TDP-43-spectrum disease biology. PMID:21944779 · 2011 · 10.1016/j.neuron.2011.09.010
Loss of nuclear TDP-43-mediated splicing creates an RNA-proteostasis bottleneck that impairs protein quality control specifically in vulnerable motor and hippocampal neurons. PMID:23382207
Loss of nuclear TDP-43-mediated splicing creates an RNA-proteostasis bottleneck that impairs protein quality control specifically in vulnerable motor and hippocampal neurons. PMID:38941189
Loss of nuclear TDP-43 function directly causes RNA splicing defects including cryptic exon inclusion in transcripts such as STMN2 PMID:30643298
Loss of nuclear TDP-43 function directly causes RNA splicing defects including cryptic exon inclusion in transcripts such as STMN2 PMID:38443601
Loss of nuclear TDP-43 function directly causes RNA splicing defects including cryptic exon inclusion in transcripts such as STMN2 PMID:39114608
A shared RNA-proteostasis bottleneck mediates disease-specific neuronal vulnerability via differential effects on distinct neuronal populations expressing the same mislocalized TDP-43 pathology PMID:23931993
TDP-43 proteinopathy severity correlates with insoluble phosphorylated TDP-43 burden across ALS, FTD, and AD/LATE independent of primary disease etiology PMID:40709649
Nuclear TDP-43 loss directly impairs splicing of STMN2 and similar neuronal transcripts by preventing TDP-43 binding to target UG-repeats in pre-mRNA. PMID:38443601
Nuclear TDP-43 loss directly impairs splicing of STMN2 and similar neuronal transcripts by preventing TDP-43 binding to target UG-repeats in pre-mRNA. PMID:32790644
A shared RNA-proteostasis bottleneck caused by TDP-43 dysfunction produces disease-specific neuronal vulnerability across ALS, FTD, and AD/LATE. PMID:37605276
A shared RNA-proteostasis bottleneck caused by TDP-43 dysfunction produces disease-specific neuronal vulnerability across ALS, FTD, and AD/LATE. PMID:38896345

Contradicting

No contradicting evidence recorded.

Top-ranked evidence

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

Supports · top 3

#1 ca8fac23-ffac-401f-8b8a-8f6e755ec6ef 0.470 trust 0.50 · rel 1.00 · 75d
#2 8afa8c83-b98e-4393-8510-d1f3d0804edd 0.470 trust 0.50 · rel 1.00 · 75d
#3 1c5afdb9-c6a8-44d0-9382-154cf18f1a62 0.235 trust 0.50 · rel 0.50 · 75d

3 total ranked · scidex.hypotheses.evidence_ranking

Cite this hypothesis

Citation

etl-backfill (2026). TDP-43 RNA-proteostasis failure across ALS, FTD, and AD/LATE. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/h-cross-synth-tdp43-rna-proteostasis

BibTeX

@misc{scidex_hypothesis_hcrosssy,
  title        = {TDP-43 RNA-proteostasis failure across ALS, FTD, and AD/LATE},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/h-cross-synth-tdp43-rna-proteostasis},
  note         = {SciDEX artifact hypothesis:h-cross-synth-tdp43-rna-proteostasis}
}