ID: h-gap-92152803-m3
Hypothesis
proteasome shuttle failure defines the therapeutic window for: How do ALS-linked UBQLN2 mutations affect its ubiquitylation-dependent stability a
The same signal may be beneficial early and damaging late.
EvidencePending (0%)📖 6 cit🗣 1 debates✓ 6 support✗ 1 oppose
✓ All Quality Gates Passed
🧪 Overview
The same signal may be beneficial early and damaging late. Testing proteasome shuttle failure with autophagy flux rescue should reveal a disease-stage interaction and define when intervention is protective versus counterproductive.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["proteasome shuttle failure<br/>Hypothesis Target"]
B["Autophagy<br/>Cited Mechanism"]
C["Cellular Response<br/>Stress or Clearance Change"]
D["Neural Circuit Effect<br/>Synapse/Glia Vulnerability"]
E["ALS<br/>Disease-Relevant Outcome"]
A --> B
B --> C
C --> D
D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix5 supports1 contradicts
Supports
UBQLN proteins in health and disease with a focus on UBQLN2 in ALS/FTD.
Supports
Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques.
Supports
Stress Granules and ALS: A Case of Causation or Correlation?
Contradicts
causal direction requires longitudinal perturbation
skeptic_round
📖 Linked Papers (13)Export BibTeX ↗
Carnitine Shuttle and Ferroptosis in Cancer.
Antioxidants (Basel) (2025) · PubMed:40867868 ↗
No figures
Endogenous retroviruses are dysregulated in ALS.
iScience (2024) · PubMed:38989463 ↗
No figures
Endogenous retroviruses are dysregulated in ALS.
iScience (2024) · PubMed:38989463 ↗
No figures
The genetics of amyotrophic lateral sclerosis.
Curr Opin Neurol (2024) · PubMed:38967083 ↗
No figures
The genetics of amyotrophic lateral sclerosis.
Curr Opin Neurol (2024) · PubMed:38967083 ↗
No figures
REM Sleep: An Unknown Indicator of Sleep Quality.
Int J Environ Res Public Health (2021) · PubMed:34948586 ↗
No figures
Diagnostic and therapeutic options in recurrent implantation failure.
F1000Res (2020) · PubMed:32266059 ↗
No figures
ALS Genetics, Mechanisms, and Therapeutics: Where Are We Now?
Front Neurosci (2019) · PubMed:31866818 ↗
No figures
Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques.
International journal of molecular sciences (2019) · PubMed:31185581 ↗
No figures
Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques.
International journal of molecular sciences (2019) · PubMed:31185581 ↗
No figures
Organ Failure Due to Systemic Injury in Acute Pancreatitis.
Gastroenterology (2019) · PubMed:30768987 ↗
No figures
Stress Granules and ALS: A Case of Causation or Correlation?
Advances in neurobiology (2018) · PubMed:29916020 ↗
No figures
🏥 Translation
🧬 3D Protein Structure — PROTEASOME
No curated PDB or AlphaFold mapping for PROTEASOME 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 proteasome shuttle failure.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
🏆 Tournament
🏆 Arenas / Elo
No arena matches recorded yet. Browse Arenas →
📊 Market Indicators
7d Trend
↔
Stable
7d Momentum
▲ 0.0%
Volatility
High
0.2212
Events (7d)
1
Price History
▲7.9%💾 Resource Usage
No resource usage or linked notebooks recorded for this hypothesis yet.
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF shuttle failure is the proximal lesion, THEN proteasome reporter clearance will slow by >=25% before motor-neuron viability drops by 10% in UBQLN2 mutant cultures. | Proteasome reporter half-life increases >=25% at a pre-viability-loss timepoint. | — no observation — | pending | 0.62 |
| IF proteasome shuttle failure defines the UBQLN2 therapeutic window, THEN early autophagy-flux rescue will lower insoluble UBQLN2 by >=30%, but delayed rescue after aggregate maturation will lower it | Early rescue reduces insoluble UBQLN2 >=30%; delayed rescue reduces insoluble UBQLN2 <10%. | — no observation — | pending | 0.58 |
🔮 Falsifiable Predictions (2)
pendingconf 62%
IF shuttle failure is the proximal lesion, THEN proteasome reporter clearance will slow by >=25% before motor-neuron viability drops by 10% in UBQLN2 mutant cultures.
Predicted outcome: Proteasome reporter half-life increases >=25% at a pre-viability-loss timepoint.
Falsification: Reporter clearance is unchanged until after viability loss or half-life increase is <5%.
pendingconf 58%
IF proteasome shuttle failure defines the UBQLN2 therapeutic window, THEN early autophagy-flux rescue will lower insoluble UBQLN2 by >=30%, but delayed rescue after aggregate maturation will lower it by <10%.
Predicted outcome: Early rescue reduces insoluble UBQLN2 >=30%; delayed rescue reduces insoluble UBQLN2 <10%.
Falsification: Early and delayed rescue have equivalent effects or early rescue fails despite restored autophagy flux.
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesis
| source | v1_phase_c_backfill |
| origin_type | debate_synthesis |
| _schema_version | 1 |
📊 Evidence Profile
Evidence Balance
+0%
Certainty
0%
Debates
0
Incoming
0
Outgoing
0
0 supporting
0 contradicting
0 neutral
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