Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in bergmann glia | 0.75 |
| chemistry Open Targets | compounds already reach it: sodium oxybate, lesogaberan, oxybate +4 | 1.00 |
| trials ClinicalTrials.gov | 3 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 2 Parkinson's papers of 186 | 0.85 |
| pathways Reactome | 5 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress GABBR1 in astrocytes; measure evoked dopamine release and dopamine transporter uptake and α-synuclein uptake and degradation, and dopamine neuron survival in co-culture.
- Cell type
- astrocytes
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- evoked dopamine release and dopamine transporter uptake
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- Rule-out
- If neither arm moves evoked dopamine release by 20% or more against non-targeting and empty-vector controls, across three independent differentiations, the hypothesis is wrong.
- Lab request
- CRISPRi knockdown and lentiviral overexpression of GABBR1 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: evoked dopamine release and dopamine transporter uptake; α-synuclein uptake and degradation, and dopamine neuron survival in co-culture. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- GABBR1 in dopamine neurons, braak-0.29 (p 0.456) → -0.44 (p 0.240)receipt 8262
- GABBR1 in astrocytes, braak-0.19 (p 0.630) → +0.25 (p 0.520)receipt 8261
Swarm cases
receipt 8262: GABBR1 in dopamine neurons, braak
- power
- full sample -0.41 (p 0.089, n 18), 95% CI -0.74 to +0.07. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.35 (p 0.150, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.22 (p 0.389, n 18). could be the mix.
- skeptic
- leave-one-out range -0.49 to -0.32, sign flips 0; without severely affected donors -0.41 (p 0.089, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABBR1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 8261: GABBR1 in astrocytes, braak
- power
- full sample -0.04 (p 0.861, n 18), 95% CI -0.50 to +0.43. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.04 (p 0.861, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.00 (p 0.997, n 18). could be the mix.
- skeptic
- leave-one-out range -0.16 to +0.10, sign flips 4; without severely affected donors -0.04 (p 0.861, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABBR1 in astrocytes.
case closed: nothing better to follow up.
Receipts
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