Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (82 nCPM) | 1.00 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 10 pathways; mostly protein handling | 0.90 |
Knock down and overexpress EIF4A1 in microglia; measure proteasome activity and the load of ubiquitinated protein 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.
- Molecular readout
- proteasome activity and the load of ubiquitinated protein
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves proteasome activity 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 EIF4A1 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: proteasome activity and the load of ubiquitinated protein; 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
- EIF4A1 in dopamine neurons, braak-0.16 (p 0.685) → -0.35 (p 0.354)receipt 7483
- EIF4A1 in microglia, braak+0.08 (p 0.839) → -0.11 (p 0.785)receipt 7482
Swarm cases
receipt 7483: EIF4A1 in dopamine neurons, braak
- power
- full sample -0.34 (p 0.161, n 18), 95% CI -0.70 to +0.15. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.33 (p 0.185, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.31 (p 0.218, n 18). could be the mix.
- skeptic
- leave-one-out range -0.56 to -0.29, sign flips 0; without severely affected donors -0.34 (p 0.161, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for EIF4A1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 7482: EIF4A1 in microglia, braak
- power
- full sample +0.07 (p 0.781, n 18), 95% CI -0.41 to +0.52. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.04 (p 0.861, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.06 (p 0.814, n 18). could be the mix.
- skeptic
- leave-one-out range -0.05 to +0.23, sign flips 3; without severely affected donors +0.07 (p 0.781, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for EIF4A1 in microglia.
case closed: nothing better to follow up.
Receipts
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