Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.12 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including oligodendrocyte progenitor cells; strongest in retinal horizontal cells | 0.75 |
| chemistry Open Targets | compounds already reach it: simpinicline, abt-560, pozanicline +13 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 6 Parkinson's papers of 366 | 0.74 |
| pathways Reactome | 3 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress CHRNA4 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 CHRNA4 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
- CHRNA4 in dopamine neurons, braak-0.27 (p 0.487) → -0.62 (p 0.078)receipt 2301
- CHRNA4 in oligodendrocytes, braak-0.02 (p 0.965) → -0.06 (p 0.869)receipt 2300
Swarm cases
receipt 2301: CHRNA4 in dopamine neurons, braak
- power
- full sample -0.42 (p 0.082, n 18), 95% CI -0.74 to +0.06. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.44 (p 0.070, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.64 (p 0.0039, n 18). not the mix.
- skeptic
- leave-one-out range -0.54 to -0.34, sign flips 0; without severely affected donors -0.42 (p 0.082, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CHRNA4 in dopamine neurons.
case closed: nothing better to follow up.
receipt 2300: CHRNA4 in oligodendrocytes, braak
- power
- full sample -0.07 (p 0.774, n 18), 95% CI -0.52 to +0.41. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.06 (p 0.807, n 18). does not hold up.
- composition
- oligodendrocytes share of nuclei vs axis +0.03 (p 0.915); controlling for it: -0.24 (p 0.337, n 18). could be the mix.
- skeptic
- leave-one-out range -0.16 to +0.04, sign flips 3; without severely affected donors -0.07 (p 0.774, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CHRNA4 in oligodendrocytes.
case closed: nothing better to follow up.
Receipts
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