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 enriched in microglia (1021 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: rosiptor | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 7 Parkinson's papers of 154 | 0.73 |
| pathways Reactome | 6 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress INPP5D 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.
- 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 INPP5D 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
- INPP5D in dopamine neurons, braak-0.55 (p 0.123) → -0.65 (p 0.058)receipt 7792
- INPP5D in microglia, braak-0.05 (p 0.894) → +0.27 (p 0.487)receipt 7791
Swarm cases
receipt 7792: INPP5D in dopamine neurons, braak
- power
- full sample -0.60 (p 0.0083, n 18), 95% CI -0.83 to -0.19. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: -0.62 (p 0.0064, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.67 (p 0.0024, n 18). not the mix.
- skeptic
- leave-one-out range -0.68 to -0.55, sign flips 0; without severely affected donors -0.60 (p 0.0083, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for INPP5D in dopamine neurons.
case closed: nothing better to follow up.
receipt 7791: INPP5D in microglia, braak
- power
- full sample +0.12 (p 0.627, n 18), 95% CI -0.36 to +0.56. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.07 (p 0.787, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.01 (p 0.956, n 18). could be the mix.
- skeptic
- leave-one-out range -0.02 to +0.24, sign flips 1; without severely affected donors +0.12 (p 0.627, n 18). fragile.
- cell type
- strongest in dopamine neurons: -0.60 (p 0.0083, n 18) vs +0.12 in microglia. proposing dopamine neurons.
- axis
- no measure beats "tracks Braak Lewy-body stage" for INPP5D in microglia.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up INPP5D · dopamine neurons · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) -0.32 p 0.248 (needs p < 2.7e-4)
Receipts
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