Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.36 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including oligodendrocyte progenitor cells; strongest in neuroendocrine cells | 0.75 |
| chemistry Open Targets | compounds already reach it: gabapentin, bepridil, suloctidil +8 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 22 Parkinson's papers of 1,040 | 0.59 |
| pathways Reactome | 2 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress CACNA1A 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 CACNA1A 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
- CACNA1A in oligodendrocytes, braak-0.37 (p 0.329) → +0.14 (p 0.718)receipt 0842
- CACNA1A in dopamine neurons, braak+0.25 (p 0.514) → -0.39 (p 0.297)receipt 0843
Swarm cases
receipt 0843: CACNA1A in dopamine neurons, braak
- power
- full sample -0.08 (p 0.741, n 18), 95% CI -0.53 to +0.40. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.08 (p 0.741, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.14 (p 0.585, n 18). could be the mix.
- skeptic
- leave-one-out range -0.21 to +0.01, sign flips 1; without severely affected donors -0.08 (p 0.741, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CACNA1A in dopamine neurons.
case closed: nothing better to follow up.
receipt 0842: CACNA1A in oligodendrocytes, braak
- power
- full sample -0.15 (p 0.555, n 18), 95% CI -0.58 to +0.34. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.16 (p 0.521, n 18). does not hold up.
- composition
- oligodendrocytes share of nuclei vs axis +0.03 (p 0.915); controlling for it: -0.30 (p 0.232, n 18). could be the mix.
- skeptic
- leave-one-out range -0.29 to -0.03, sign flips 0; without severely affected donors -0.15 (p 0.555, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CACNA1A in oligodendrocytes.
case closed: nothing better to follow up.
Receipts
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