STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43…

Proposed by etl-backfill

TARDBP als market 67% open
Compare across mechanisms →
Composite
76%
Novelty
55%
Feasibility
75%
Impact
88%
Mechanistic
94%
Druggability
—
Safety
—
Confidence
60%

Mechanistic description

Loss of nuclear TDP-43 in ALS motor neurons first manifests as aberrant inclusion of the STMN2 cryptic exon 2a, producing a truncated non-functional STMN2 protein that impairs microtubule repair at the axon. This splicing defect precedes detectable cytoplasmic TDP-43 aggregation by at least 48h in iPSC motor neurons subjected to TDP-43 depletion, establishing STMN2 cryptic exon inclusion as the earliest measurable loss-of-function event. Restoring STMN2 function with antisense oligonucleotides should delay axonal degeneration even when cytoplasmic aggregates have already formed.

Mechanism / pathway

  1. TARDBP
  2. TDP-43 splicing regulation / axon maintenance
  3. als

Evidence for (5)

  • [Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options].

    PMID:34879411 2021 Dtsch Med Wochenschr

  • ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair.

    PMID:30643292 2019 Nat Neurosci

  • The genetics of amyotrophic lateral sclerosis.

    PMID:38967083 2024 Curr Opin Neurol

  • Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.

    PMID:36927019 2023 Science

  • TDP-43 Pathology in Alzheimer's Disease.

    PMID:34930382 2021 Mol Neurodegener

Evidence against (2)

Evidence matrix

5 supporting 0 contradicting
100% supporting

Supporting

  • [Amyotrophic lateral sclerosis (ALS) - diagnosis, course of disease and treatment options]. PMID:34879411 · 2021 · Dtsch Med Wochenschr
  • ALS-implicated protein TDP-43 sustains levels of STMN2, a mediator of motor neuron growth and repair. PMID:30643292 · 2019 · Nat Neurosci
  • The genetics of amyotrophic lateral sclerosis. PMID:38967083 · 2024 · Curr Opin Neurol
  • Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. PMID:36927019 · 2023 · Science
  • TDP-43 Pathology in Alzheimer's Disease. PMID:34930382 · 2021 · Mol Neurodegener

Contradicting

No contradicting evidence recorded.

Cite this hypothesis

Cite this hypothesis
Citation

etl-backfill (2026). STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43…. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/ec8b839c-6440-45dc-aff6-5edea1fd2d6d

BibTeX 
@misc{scidex_hypothesis_ec8b839c,
  title        = {STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43…},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/ec8b839c-6440-45dc-aff6-5edea1fd2d6d},
  note         = {SciDEX artifact hypothesis:ec8b839c-6440-45dc-aff6-5edea1fd2d6d}
}

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