SFPQ Paralog Displacement Triggers Cryptic Polyadenylation and Global RNA Stability Loss in ALS Motor Neurons
🧪 Overview
SFPQ (Splicing Factor Proline-Glutamine Rich) is a non-POU domain octamer binding protein (NONO) family member that functions as an essential splicing factor and RNA processing scaffold. This hypothesis proposes that in ALS motor neurons, TDP-43 cytoplasmic mislocalization causes partial depletion of nuclear SFPQ from its normal genomic loci, triggering expression of a set of germline-era SFPQ-paralog (PSP1/NONO) genes normally silenced in differentiated neurons. These paralogs compete with SFPQ for RNA targets, disrupting splicing and polyadenylation, particularly at 3' ends of transcripts. The mechanistic prediction is that nuclear SFPQ loss activates a retrotransposon-derived promoter upstream of PSP1 (a SFPQ paralog on chromosome X), ectopically expressing PSP1 protein that sequesters a subset of SFPQ-dependent RNAs (including those with unusual 3' UTR structures). In TDP-43-depleted motor neurons, RNA-seq shows activation of PSP1 expression (10-fold upregulation), widespread 3' end processing defects (increased usage of cryptic poly(A) sites), and global mRNA destabilization (median mRNA half-life reduced from 8.2h to 4.7h).
...🧬 Mechanism
Curated pathway from expert analysis
flowchart TD
A["TDP43 Nuclear Depletion<br/>ALS FTD RNA Binding Loss"]
B["SFPQ Locus Occupancy Reduced<br/>RNA Scaffold Weakening"]
C["NONO PSP1 Paralog Expression<br/>Competing Nuclear Complexes"]
D["CPSF PABPN1 Polyadenylation Shift<br/>Cryptic APA Usage"]
E["Short 3 Prime UTR Transcripts<br/>RNA Stability Loss"]
F["Motor Neuron Transcriptome Fragility<br/>Axonal Program Failure"]
G["ALS Degeneration<br/>RNA Processing Collapse"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
style A fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — SFPQ
No curated PDB or AlphaFold mapping for SFPQ yet. Search RCSB →
💉 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 SFPQ,NONO,PSP1,TARDBP,poly(A) machinery,CPSF,PABPN1.
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.
🔮 Predictions
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF TDP-43 nuclear localization is restored via AAV-mediated expression of NLS-TDP-43 in TDP-43-depleted motor neurons derived from ALS patients with TDP-43 pathology, THEN PSP1 mRNA expression will de | PSP1 mRNA levels decrease to ≤0.5-fold of TDP-43-depleted baseline (target: <2-fold above normal differentiated neurons) as measured by qRT-PCR with isoform-spe | — no observation — | pending | 0.72 |
| IF combined treatment with PSP1-targeting ASO (targeting unique 5' UTR) and NLS-TDP-43 AAV is administered to TDP-43-depleted motor neuron cultures, THEN median mRNA half-life will increase to ≥6.5 ho | Median mRNA half-life recovers to ≥80% of normal (≥6.5h from baseline 4.7h) and ratio of cryptic to canonical poly(A) site usage decreases by ≥50% as measured b | — no observation — | pending | 0.65 |
▸Metadatasource: v1_phase_c_backfill · origin_type: auto-generated
| source | v1_phase_c_backfill |
| origin_type | auto-generated |
| _schema_version | 1 |