Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.07 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (2144 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: ezogabine, tedisamil, amifampridine +5 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 2 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress KCNQ3 in microglia; measure evoked dopamine release and dopamine transporter uptake and uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release).
- Cell type
- microglia
- 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
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- 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 KCNQ3 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: evoked dopamine release and dopamine transporter uptake; uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release). Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- KCNQ3 in dopamine neurons, braak-0.47 (p 0.197) → -0.69 (p 0.038)receipt 3975
- KCNQ3 in microglia, braak+0.55 (p 0.123) → -0.11 (p 0.778)receipt 3974
Swarm cases
receipt 3975: KCNQ3 in dopamine neurons, braak
- power
- full sample -0.55 (p 0.017, n 18), 95% CI -0.81 to -0.12. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: -0.61 (p 0.0069, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.62 (p 0.0057, n 18). not the mix.
- skeptic
- leave-one-out range -0.62 to -0.50, sign flips 0; without severely affected donors -0.55 (p 0.017, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNQ3 in dopamine neurons.
case closed: nothing better to follow up.
receipt 3974: KCNQ3 in microglia, braak
- power
- full sample +0.22 (p 0.384, n 18), 95% CI -0.28 to +0.62. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.24 (p 0.341, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.25 (p 0.315, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.33, sign flips 0; without severely affected donors +0.22 (p 0.384, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNQ3 in microglia.
case closed: nothing better to follow up.
Receipts
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