Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.30 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 besylate, thiamylal, primidone +72 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 1 Parkinson's papers of 304 | 0.91 |
| pathways Reactome | 1 pathway; mostly dopamine synapse | 1.00 |
Knock down and overexpress GABRA2 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 GABRA2 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
- GABRA2 in astrocytes, braak+0.09 (p 0.825) → +0.20 (p 0.597)receipt 1270
- GABRA2 in dopamine neurons, braak+0.26 (p 0.493) → +0.54 (p 0.137)receipt 1271
Swarm cases
receipt 1271: GABRA2 in dopamine neurons, braak
- power
- full sample +0.33 (p 0.176, n 18), 95% CI -0.16 to +0.69. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.34 (p 0.173, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.34 (p 0.173, n 18). could be the mix.
- skeptic
- leave-one-out range +0.24 to +0.48, sign flips 0; without severely affected donors +0.33 (p 0.176, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRA2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 1270: GABRA2 in astrocytes, braak
- power
- full sample +0.08 (p 0.761, n 18), 95% CI -0.40 to +0.53. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.08 (p 0.761, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.12 (p 0.640, n 18). could be the mix.
- skeptic
- leave-one-out range -0.06 to +0.19, sign flips 3; without severely affected donors +0.08 (p 0.761, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRA2 in astrocytes.
case closed: nothing better to follow up.
Receipts
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