Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.06 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including oligodendrocyte progenitor cells; strongest in myonuclei | 0.75 |
| chemistry Open Targets | compounds already reach it: dalfampridine, amifampridine, amifampridine phosphate +3 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 1 Parkinson's papers of 27 | 0.91 |
| pathways Reactome | 2 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress KCNS3 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 KCNS3 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
- KCNS3 in oligodendrocytes, braak+0.70 (p 0.035) → -0.22 (p 0.567)receipt 4524
- KCNS3 in dopamine neurons, braak+0.62 (p 0.074) → +0.62 (p 0.074)receipt 4525
Swarm cases
receipt 4525: KCNS3 in dopamine neurons, braak
- power
- full sample +0.55 (p 0.018, n 18), 95% CI +0.11 to +0.81. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.55 (p 0.018, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.57 (p 0.013, n 18). not the mix.
- skeptic
- leave-one-out range +0.49 to +0.63, sign flips 0; without severely affected donors +0.55 (p 0.018, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNS3 in dopamine neurons.
case closed: nothing better to follow up.
receipt 4524: KCNS3 in oligodendrocytes, braak
- power
- full sample +0.17 (p 0.498, n 18), 95% CI -0.32 to +0.59. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.24 (p 0.332, n 18). does not hold up.
- composition
- oligodendrocytes share of nuclei vs axis +0.03 (p 0.915); controlling for it: +0.09 (p 0.735, n 18). could be the mix.
- skeptic
- leave-one-out range +0.08 to +0.32, sign flips 0; without severely affected donors +0.17 (p 0.498, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNS3 in oligodendrocytes.
case closed: nothing better to follow up.
Receipts
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