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 microglia; strongest in proximal tubule cells | 0.75 |
| chemistry Open Targets | compounds already reach it: tedisamil, dalfampridine, amifampridine phosphate +3 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 2 Parkinson's papers of 77 | 0.85 |
| pathways Reactome | 1 pathway; mostly dopamine synapse | 1.00 |
Knock down and overexpress KCNC3 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 KCNC3 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
- KCNC3 in microglia, braak-0.72 (p 0.027) → +0.05 (p 0.891)receipt 4718
- KCNC3 in dopamine neurons, braak-0.63 (p 0.068) → -0.19 (p 0.618)receipt 4719
Swarm cases
receipt 4719: KCNC3 in dopamine neurons, braak
- power
- full sample -0.50 (p 0.036, n 18), 95% CI -0.78 to -0.04. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: -0.47 (p 0.051, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.60 (p 0.0080, n 18). not the mix.
- skeptic
- leave-one-out range -0.63 to -0.43, sign flips 0; without severely affected donors -0.50 (p 0.036, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNC3 in dopamine neurons.
case closed: nothing better to follow up.
receipt 4718: KCNC3 in microglia, braak
- power
- full sample -0.46 (p 0.052, n 18), 95% CI -0.77 to +0.00. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.47 (p 0.049, n 18). holds up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.54 (p 0.020, n 18). not the mix.
- skeptic
- leave-one-out range -0.62 to -0.40, sign flips 0; without severely affected donors -0.46 (p 0.052, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCNC3 in microglia.
case closed: nothing better to follow up.
Receipts
loading the receipts