ID: h-c98d1cb4e7
Hypothesis
AAV-mediated RGS6 re-expression in SNpc after pathology onset
Restore RGS6 in substantia nigra pars compacta dopaminergic neurons after established alpha-synuclein pathology to test whether RGS6 loss is not only necessary but therapeutically reversible.
EvidencePending (0%)📖 0 cit🗣 1 debates✓ 7 support✗ 3 oppose
✓ All Quality Gates Passed
🧪 Overview
Restore RGS6 in substantia nigra pars compacta dopaminergic neurons after established alpha-synuclein pathology to test whether RGS6 loss is not only necessary but therapeutically reversible. The decisive experiment is delayed intervention in PFF or AAV-SNCA models with unbiased stereology, terminal preservation, dopamine physiology, and catalytically dead RGS6 controls.
🧬 Mechanism
🧬 Curated Mechanism Pathway
Curated pathway from expert analysis
flowchart TD
A["RGS6/Galphao Interaction<br/>GTPase-Activating Protein Recruitment"]
B["GPCR Signaling Suppression<br/>Gi/o-Mediated cAMP Reduction"]
C["DRD2 and ADORA2A Desensitization<br/>Dopaminergic Tone Modulation"]
D["Neuronal Survival<br/>Anti-apoptotic Program Maintenance"]
E["Dopaminergic Neuroprotection<br/>Substantia Nigra Viability"]
F["RGS6 Loss<br/>GPCR Hyperactivation and Nigral Degeneration"]
A --> B
B --> C
C --> D
D --> E
F -.->|"triggers"| E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style E fill:#1b5e20,stroke:#81c784,color:#81c784
style F fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a⚖️ Evidence
⚖️ Evidence Matrix7 supports3 contradicts
Supports
RGS6 deficiency causes age-dependent nigral dopaminergic degeneration, alpha-synuclein accumulation, hyperactive D2 autoreceptor signaling, and reduced cAMP signaling, making RGS6 restoration the most direct therapeutic test of the causal axis.
Supports
Earlier mouse work independently linked loss of Rgs6 to Parkinsonian dopaminergic pathology, supporting necessity of endogenous RGS6 for nigrostriatal integrity.
Supports
RGS6 suppresses Ras-induced cellular transformation by facilitating Tip60-mediated Dnmt1 degradation and promoting apoptosis.
Supports
Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in a mouse model of Alzheimer's disease.
Supports
RGS6 drives cardiomyocyte death following nucleolar stress by suppressing Nucleolin/miRNA-21.
Supports
RGS6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in an Alzheimer's mouse model.
Supports
RGS6 suppresses TGF-β-induced epithelial-mesenchymal transition in non-small cell lung cancers via a novel mechanism dependent on its interaction with SMAD4.
Contradicts
Loss-of-function necessity does not establish that gain-of-function is safe or sufficient, especially once degeneration is established.
Contradicts
RGS6 has been reported to promote mitochondrial and caspase-linked apoptosis in other systems, raising a nontrivial safety liability for overexpression.
Contradicts
Additional studies also support pro-apoptotic RGS6 signaling, reinforcing concern that overexpression could worsen neuronal loss rather than rescue it.
📖 Linked Papers
No linked papers recorded for this hypothesis yet.
🏥 Translation
🧬 3D Protein Structure — RGS6
No curated PDB or AlphaFold mapping for RGS6 yet. Search RCSB →
🧠 GTEx v10 Brain ExpressionJSON
Median TPM across 13 brain regions for RGS6 from GTEx v10.
💉 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 RGS6.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
💰 Estimated Development
Cost
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Timeline
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📊 Market Indicators
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Volatility
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Events (7d)
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LLM Tokens
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$0.0353
Total Cost
$0.0353
🔮 Predictions
🔎 Predictions vs Observations2 predictions · 0 with recorded observations
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF adult C57BL/6J mice receive bilateral AAV9-RGS6 injections into SNpc 60 days after AAV-SNCA overexpression (when alpha-synuclein pathology is established), THEN treated mice will exhibit significan | Motor function improvement (rotarod latency ≥25 s vs. ≤18 s in controls; akinesia latency ≥120 s vs. ≤80 s in controls), with behavioral rescue maintained at 12 | — no observation — | pending | 0.65 |
| IF adult C57BL/6J mice receive bilateral AAV9-RGS6 injection into SNpc 45 days after PFF α-synuclein seeding (when phosphorylated α-synuclein aggregates are established), THEN stereological counting w | TH+ neuron count in SNpc ≥5,000 cells and striatal DA ≥0.8 μg/mg tissue, vs. ≤3,500 TH+ cells and ≤0.5 μg/mg in PFF + AAV-GFP controls. | — no observation — | pending | 0.55 |
🔮 Falsifiable Predictions (2)
pendingconf 65%
IF adult C57BL/6J mice receive bilateral AAV9-RGS6 injections into SNpc 60 days after AAV-SNCA overexpression (when alpha-synuclein pathology is established), THEN treated mice will exhibit significantly preserved rotarod latency (≥40% improvement vs. AAV-SNCA + AAV-GFP controls) and reduced parkins
Predicted outcome: Motor function improvement (rotarod latency ≥25 s vs. ≤18 s in controls; akinesia latency ≥120 s vs. ≤80 s in controls), with behavioral rescue mainta
Falsification: No significant difference in motor behavioral scores between AAV-RGS6 and AAV-GFP control groups (p > 0.05, two-way ANOVA with Bonferroni correction); or accelerated motor decline suggesting toxicity.
pendingconf 55%
IF adult C57BL/6J mice receive bilateral AAV9-RGS6 injection into SNpc 45 days after PFF α-synuclein seeding (when phosphorylated α-synuclein aggregates are established), THEN stereological counting will reveal significantly higher SNpc TH+ neuron survival (≥60% vs. ≤35% in PFF + AAV-GFP) and striat
Predicted outcome: TH+ neuron count in SNpc ≥5,000 cells and striatal DA ≥0.8 μg/mg tissue, vs. ≤3,500 TH+ cells and ≤0.5 μg/mg in PFF + AAV-GFP controls.
Falsification: RGS6 re-expression fails to preserve TH+ neurons (≤40% survival, p > 0.05 vs. PFF controls) or striatal dopamine content (≤55% of sham); or stereological counts show no difference between catalyticall
▸Metadatasource: v1_phase_c_backfill · origin_type: debate_synthesizer
| source | v1_phase_c_backfill |
| origin_type | debate_synthesizer |
| _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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