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 in microglia (307 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: giripladib | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 318 | 0.91 |
| pathways Reactome | 13 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress PLA2G4A in microglia; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- 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 PLA2G4A in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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
- PLA2G4A in dopamine neurons, braak+0.21 (p 0.586) → +0.11 (p 0.787)receipt 4169
- PLA2G4A in microglia, braak-0.08 (p 0.842) → -0.13 (p 0.732)receipt 4168
Swarm cases
receipt 4169: PLA2G4A in dopamine neurons, braak
- power
- full sample +0.21 (p 0.398, n 18), 95% CI -0.28 to +0.62. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.23 (p 0.351, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.29 (p 0.235, n 18). could be the mix.
- skeptic
- leave-one-out range +0.09 to +0.38, sign flips 0; without severely affected donors +0.21 (p 0.398, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PLA2G4A in dopamine neurons.
case closed: nothing better to follow up.
receipt 4168: PLA2G4A in microglia, braak
- power
- full sample -0.07 (p 0.774, n 18), 95% CI -0.52 to +0.41. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.05 (p 0.854, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.01 (p 0.969, n 18). could be the mix.
- skeptic
- leave-one-out range -0.22 to +0.04, sign flips 3; without severely affected donors -0.07 (p 0.774, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PLA2G4A in microglia.
case closed: nothing better to follow up.
Receipts
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