Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.54 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including brain inhibitory neurons; strongest in cardiomyocytes | 0.75 |
| chemistry Open Targets | compounds already reach it: alcuronium, darifenacin hydrobromide, glycopyrronium tosylate +27 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 3 Parkinson's papers of 210 | 0.82 |
| pathways Reactome | 4 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress CHRM2 in dopamine neurons; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position and survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils.
- Cell type
- dopamine neurons
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- Functional readout
- survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils
- Rule-out
- If neither arm moves LRRK2 kinase activity (pT73-Rab10) 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 CHRM2 in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Earlier readings: 2026-10-26 0.63; 2026-10-25 0.63; 2026-10-24 0.63; 2026-10-23 0.63.
Sealed predictions
- CHRM2 in dopamine neurons, braak+0.55 (p 0.123) → -0.31 (p 0.414)receipt 0594
- CHRM2 in dopamine neurons, braak+0.44 (p 0.004) → +0.28 (p 0.076)receipt 0141
- CHRM2 in dopamine neurons, resilience-0.43 (p 0.133) → +0.15 (p 0.584)receipt 0142
Swarm cases
receipt 0594: CHRM2 in dopamine neurons, braak
- power
- full sample +0.17 (p 0.504, n 18), 95% CI -0.32 to +0.59. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.11 (p 0.652, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.16 (p 0.538, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.26, sign flips 0; without severely affected donors +0.17 (p 0.504, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CHRM2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0142: CHRM2 in dopamine neurons, resilience
- power
- full sample -0.11 (p 0.570, n 55), 95% CI -0.37 to +0.16. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: -0.11 (p 0.570, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.10 (p 0.628, n 55). could be the mix.
- skeptic
- leave-one-out range -0.20 to -0.03, sign flips 0; without severely affected donors -0.13 (p 0.528, n 46). fragile.
- cell type
- strongest in OPCs: +0.53 (p 0.0071, n 55) vs -0.11 in dopamine neurons. proposing OPCs.
- axis
- braak beats resilience for CHRM2 in dopamine neurons: +0.37 (p 5.7e-4, n 84). proposing braak.
follow-up registered; not confirmed in ventral tegmental area.
follow-up CHRM2 · OPCs · resilience: ventral tegmental area +0.34 p 0.054 (needs p < 0.0024)
receipt 0141: CHRM2 in dopamine neurons, braak
- power
- full sample +0.37 (p 5.7e-4, n 84), 95% CI +0.17 to +0.54. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for age, sex and PMI: +0.39 (p 2.2e-4, n 84). holds up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: +0.13 (p 0.229, n 84). could be the mix.
- skeptic
- leave-one-out range +0.35 to +0.40, sign flips 0; without severely affected donors +0.42 (p 1.8e-4, n 75). robust.
- cell type
- no other cell group does better.
- axis
- nigra beats braak for CHRM2 in dopamine neurons: +0.36 (p 6.9e-4, n 84). proposing nigra.
case closed: every proposal failed a challenge.
Receipts
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