Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.35 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including oligodendrocyte progenitor cells; strongest in choroid plexus epithelial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: methohexital, sevoflurane, padsevonil +71 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 1 Parkinson's papers of 136 | 0.91 |
| pathways Reactome | 1 pathway; mostly dopamine synapse | 1.00 |
Knock down and overexpress GABRA3 in oligodendrocytes; measure evoked dopamine release and dopamine transporter uptake and α-synuclein uptake and myelin basic protein output under oxidative stress.
- Cell type
- oligodendrocytes
- 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 myelin basic protein output under oxidative stress
- 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 GABRA3 in iPSC-derived oligodendrocytes; n = 3 differentiations; readouts: evoked dopamine release and dopamine transporter uptake; α-synuclein uptake and myelin basic protein output under oxidative stress. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- GABRA3 in oligodendrocytes, braak-0.22 (p 0.569) → +0.53 (p 0.138)receipt 0902
- GABRA3 in dopamine neurons, braak+0.55 (p 0.127) → +0.41 (p 0.276)receipt 0903
Swarm cases
receipt 0903: GABRA3 in dopamine neurons, braak
- power
- full sample +0.43 (p 0.079, n 18), 95% CI -0.05 to +0.74. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.70 (p 0.0012, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.71 (p 9.6e-4, n 18). not the mix.
- skeptic
- leave-one-out range +0.34 to +0.57, sign flips 0; without severely affected donors +0.43 (p 0.079, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRA3 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0902: GABRA3 in oligodendrocytes, braak
- power
- full sample +0.10 (p 0.702, n 18), 95% CI -0.39 to +0.54. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.17 (p 0.498, n 18). does not hold up.
- composition
- oligodendrocytes share of nuclei vs axis +0.03 (p 0.915); controlling for it: +0.26 (p 0.302, n 18). could be the mix.
- skeptic
- leave-one-out range -0.01 to +0.25, sign flips 2; without severely affected donors +0.10 (p 0.702, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRA3 in oligodendrocytes.
case closed: nothing better to follow up.
Receipts
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