Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (376 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: carfilzomib, ixazomib citrate, oprozomib +4 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 4 Parkinson's papers of 111 | 0.79 |
| pathways Reactome | 69 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress PSMA1 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 PSMA1 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
- PSMA1 in dopamine neurons, braak+0.18 (p 0.651) → +0.00 (p 1.000)receipt 8953
- PSMA1 in microglia, braak-0.79 (p 0.011) → -0.07 (p 0.849)receipt 8952
Swarm cases
receipt 8953: PSMA1 in dopamine neurons, braak
- power
- full sample +0.02 (p 0.935, n 18), 95% CI -0.45 to +0.48. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.13 (p 0.621, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.11 (p 0.652, n 18). could be the mix.
- skeptic
- leave-one-out range -0.12 to +0.11, sign flips 6; without severely affected donors +0.02 (p 0.935, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PSMA1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 8952: PSMA1 in microglia, braak
- power
- full sample -0.44 (p 0.070, n 18), 95% CI -0.75 to +0.04. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.42 (p 0.082, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.42 (p 0.082, n 18). could be the mix.
- skeptic
- leave-one-out range -0.53 to -0.35, sign flips 0; without severely affected donors -0.44 (p 0.070, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PSMA1 in microglia.
case closed: nothing better to follow up.
Receipts
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