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, including microglia; strongest in megakaryocytes | 0.75 |
| chemistry Open Targets | compounds already reach it: vecabrutinib, tolebrutinib, pirtobrutinib +21 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 6 Parkinson's papers of 5,513 | 0.74 |
| pathways Reactome | 14 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress BTK 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 BTK 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
- BTK in dopamine neurons, braak-0.22 (p 0.567) → +0.54 (p 0.135)receipt 7514
- BTK in microglia, braak-0.18 (p 0.648) → +0.62 (p 0.074)receipt 7513
Swarm cases
receipt 7514: BTK in dopamine neurons, braak
- power
- full sample +0.01 (p 0.983, n 18), 95% CI -0.46 to +0.47. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.06 (p 0.807, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.05 (p 0.854, n 18). could be the mix.
- skeptic
- leave-one-out range -0.11 to +0.13, sign flips 9; without severely affected donors +0.01 (p 0.983, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for BTK in dopamine neurons.
case closed: nothing better to follow up.
receipt 7513: BTK in microglia, braak
- power
- full sample -0.06 (p 0.814, n 18), 95% CI -0.51 to +0.42. 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: -0.07 (p 0.794, n 18). could be the mix.
- skeptic
- leave-one-out range -0.20 to +0.05, sign flips 3; without severely affected donors -0.06 (p 0.814, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for BTK in microglia.
case closed: nothing better to follow up.
Receipts
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