Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.37 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in brain inhibitory neurons (153 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: methaqualone hydrochloride, adipiplon, zopiclone +70 | 1.00 |
| trials ClinicalTrials.gov | 3 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 1 pathway; mostly dopamine synapse | 1.00 |
Knock down and overexpress GABRA4 in dopamine neurons; measure evoked dopamine release and dopamine transporter uptake and survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils.
- Cell type
- dopamine neurons
- 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
- survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils
- 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 GABRA4 in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: evoked dopamine release and dopamine transporter uptake; survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- GABRA4 in dopamine neurons, braak+0.75 (p 0.019) → -0.44 (p 0.240)receipt 0759
Swarm cases
receipt 0759: GABRA4 in dopamine neurons, braak
- power
- full sample +0.11 (p 0.658, n 18), 95% CI -0.37 to +0.55. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.14 (p 0.579, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.13 (p 0.621, n 18). could be the mix.
- skeptic
- leave-one-out range -0.01 to +0.27, sign flips 1; without severely affected donors +0.11 (p 0.658, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRA4 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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