Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.44 (overall 0.30) | 0.44 |
| cell type Human Protein Atlas | group enriched outside the brain (retinal bipolar cells) | 0.10 |
| chemistry Open Targets | compounds already reach it: terodiline, mibefradil, suvecaltamide +16 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 5 Parkinson's papers of 274 | 0.76 |
| pathways Reactome | 2 pathways; mostly other | 0.30 |
Knock down and overexpress CACNA1G in a dopamine neuron, astrocyte and microglia tri-culture; measure a transcriptome-wide state shift (bulk RNA-seq) and dopamine neuron survival after α-synuclein fibril challenge.
- Cell type
- a dopamine neuron, astrocyte and microglia tri-culture
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- a transcriptome-wide state shift (bulk RNA-seq)
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves a transcriptome-wide state shift (bulk RNA-seq) 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 CACNA1G in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); dopamine neuron survival after α-synuclein fibril challenge. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- CACNA1G in dopamine neurons, braak-0.78 (p 0.013) → +0.10 (p 0.802)receipt 1262
Swarm cases
receipt 1262: CACNA1G in dopamine neurons, braak
- power
- full sample -0.31 (p 0.204, n 18), 95% CI -0.68 to +0.18. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.29 (p 0.239, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.48 (p 0.042, n 18). not the mix.
- skeptic
- leave-one-out range -0.47 to -0.23, sign flips 0; without severely affected donors -0.31 (p 0.204, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CACNA1G in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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