Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.04 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in neutrophils | 0.75 |
| chemistry Open Targets | compounds already reach it: leniolisib phosphate, pf-04691502, duvelisib monohydrate +43 | 1.00 |
| 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 | 14 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress PIK3CD 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 PIK3CD 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
- PIK3CD in dopamine neurons, braak+0.00 (p 1.000) → -0.43 (p 0.244)receipt 6257
- PIK3CD in microglia, braak-0.18 (p 0.651) → -0.53 (p 0.145)receipt 6256
Swarm cases
receipt 6257: PIK3CD in dopamine neurons, braak
- power
- full sample -0.23 (p 0.365, n 18), 95% CI -0.63 to +0.27. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.25 (p 0.310, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.32 (p 0.198, n 18). could be the mix.
- skeptic
- leave-one-out range -0.38 to -0.12, sign flips 0; without severely affected donors -0.23 (p 0.365, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PIK3CD in dopamine neurons.
case closed: nothing better to follow up.
receipt 6256: PIK3CD in microglia, braak
- power
- full sample -0.17 (p 0.509, n 18), 95% CI -0.59 to +0.33. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.21 (p 0.408, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.22 (p 0.384, n 18). could be the mix.
- skeptic
- leave-one-out range -0.31 to -0.07, sign flips 0; without severely affected donors -0.17 (p 0.509, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PIK3CD in microglia.
case closed: nothing better to follow up.
Receipts
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