Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.34 (overall 0.21) | 0.34 |
| cell type Human Protein Atlas | group enriched in microglia (1603 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: ticagrelor, elinogrel, cangrelor tetrasodium +9 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 8 Parkinson's papers of 384 | 0.71 |
| pathways Reactome | 3 pathways; mostly other | 0.30 |
Knock down and overexpress P2RY12 in microglia; measure a transcriptome-wide state shift (bulk RNA-seq) 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
- a transcriptome-wide state shift (bulk RNA-seq)
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves a transcriptome-wide state shift (bulk RNA-seq) 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 P2RY12 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); 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
- P2RY12 in dopamine neurons, braak+0.01 (p 0.982) → +0.03 (p 0.938)receipt 1974
- P2RY12 in microglia, braak+0.49 (p 0.184) → -0.19 (p 0.630)receipt 1973
Swarm cases
receipt 1974: P2RY12 in dopamine neurons, braak
- power
- full sample -0.03 (p 0.894, n 18), 95% CI -0.49 to +0.44. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.11 (p 0.664, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.12 (p 0.640, n 18). could be the mix.
- skeptic
- leave-one-out range -0.16 to +0.08, sign flips 5; without severely affected donors -0.03 (p 0.894, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for P2RY12 in dopamine neurons.
case closed: nothing better to follow up.
receipt 1973: P2RY12 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: +0.22 (p 0.384, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.35 (p 0.156, n 18). could be the mix.
- skeptic
- leave-one-out range +0.15 to +0.40, 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 P2RY12 in microglia.
case closed: nothing better to follow up.
Receipts
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