Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | group enriched, including microglia; strongest in tuft cells | 0.75 |
| chemistry Open Targets | compounds already reach it: meclofenamic acid, zileuton, sulfasalazine +8 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 2 Parkinson's papers of 712 | 0.85 |
| pathways Reactome | 15 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress ALOX5 in microglia; measure IL-1β and TNF release and surface HLA-DR 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
- IL-1β and TNF release and surface HLA-DR
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves IL-1β 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 ALOX5 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; 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
- ALOX5 in microglia, braak-0.29 (p 0.442) → -0.61 (p 0.078)receipt 10922
- ALOX5 in dopamine neurons, braak-0.58 (p 0.102) → -0.16 (p 0.685)receipt 10923
Swarm cases
receipt 10923: ALOX5 in dopamine neurons, braak
- power
- full sample -0.33 (p 0.179, n 18), 95% CI -0.69 to +0.16. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.34 (p 0.161, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.42 (p 0.086, n 18). could be the mix.
- skeptic
- leave-one-out range -0.48 to -0.25, sign flips 0; without severely affected donors -0.33 (p 0.179, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ALOX5 in dopamine neurons.
case closed: nothing better to follow up.
receipt 10922: ALOX5 in microglia, braak
- power
- full sample -0.40 (p 0.101, n 18), 95% CI -0.73 to +0.08. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.34 (p 0.170, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.39 (p 0.109, n 18). could be the mix.
- skeptic
- leave-one-out range -0.50 to -0.30, sign flips 0; without severely affected donors -0.40 (p 0.101, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ALOX5 in microglia.
case closed: nothing better to follow up.
Receipts
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