STMN2 Cryptic Exon Inclusion is the Earliest Loss-of-Function Marker of TDP-43 Nuclear Depletion in ALS Motor Neurons
🧪 Overview
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
Curated pathway from expert analysis
flowchart TD
A["TDP43 Nuclear Depletion<br/>Early ALS Event"]
B["STMN2 Cryptic Exon Inclusion<br/>Aberrant Splicing"]
C["Truncated STMN2 Transcript<br/>Loss of Functional Protein"]
D["Microtubule Repair Deficit<br/>Axon Maintenance Failure"]
E["Distal Axon Degeneration<br/>Motor Neuron Die Back"]
F["ASO STMN2 Rescue<br/>Splicing Correction Strategy"]
G["Early Biomarker Window<br/>Before TDP43 Aggregation"]
A --> B
B --> C
C --> D
D --> E
F -.->|"rescues"| B
G -.->|"detects"| B
style B fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style F fill:#1b5e20,stroke:#81c784,color:#81c784⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — TARDBP
💉 Clinical Trials
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for TARDBP.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
📊 Market Indicators
💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
▸Metadata
| _origin | {'url': None, 'type': 'internal', 'tracked_at': '2026-04-28T14:38:33.698535'} |
| 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 th |
| _schema_version | 1 |