Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.37 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in innate lymphoid cells | 0.75 |
| chemistry Open Targets | compounds already reach it: zafirlukast, montelukast, montelukast sodium +2 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 4 pathways; mostly other | 0.30 |
Knock down and overexpress CYSLTR1 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 CYSLTR1 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
- CYSLTR1 in dopamine neurons, braak+0.11 (p 0.787) → +0.58 (p 0.102)receipt 0817
- CYSLTR1 in microglia, braak-0.03 (p 0.946) → -0.05 (p 0.893)receipt 0816
Swarm cases
receipt 0817: CYSLTR1 in dopamine neurons, braak
- power
- full sample +0.31 (p 0.204, n 18), 95% CI -0.18 to +0.68. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.63 (p 0.0055, n 18). holds 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 +0.22 to +0.43, sign flips 0; without severely affected donors +0.31 (p 0.204, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CYSLTR1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0816: CYSLTR1 in microglia, braak
- power
- full sample -0.03 (p 0.908, n 18), 95% CI -0.49 to +0.44. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.01 (p 0.976, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.01 (p 0.976, n 18). could be the mix.
- skeptic
- leave-one-out range -0.13 to +0.12, sign flips 5; without severely affected donors -0.03 (p 0.908, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CYSLTR1 in microglia.
case closed: nothing better to follow up.
Receipts
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