Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.44 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: remimazolam, sevoflurane, cipepofol +72 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 2 Parkinson's papers of 125 | 0.85 |
| pathways Reactome | 2 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress GABRB1 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 GABRB1 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
- GABRB1 in astrocytes, braak-0.23 (p 0.549) → -0.10 (p 0.790)receipt 0437
- GABRB1 in dopamine neurons, braak+0.11 (p 0.775) → +0.12 (p 0.767)receipt 0438
Swarm cases
receipt 0438: GABRB1 in dopamine neurons, braak
- power
- full sample +0.20 (p 0.418, n 18), 95% CI -0.29 to +0.61. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.20 (p 0.418, 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 0.379, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.38, sign flips 0; without severely affected donors +0.20 (p 0.418, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRB1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0437: GABRB1 in astrocytes, braak
- power
- full sample -0.23 (p 0.355, n 18), 95% CI -0.63 to +0.26. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.21 (p 0.393, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.01 (p 0.962, n 18). could be the mix.
- skeptic
- leave-one-out range -0.38 to -0.14, sign flips 0; without severely affected donors -0.23 (p 0.355, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRB1 in astrocytes.
case closed: nothing better to follow up.
Receipts
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