Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.06 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in podocytes | 0.75 |
| 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 | 2 Parkinson's papers of 182 | 0.85 |
| pathways Reactome | 17 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress ARRB1 in microglia; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves LRRK2 kinase activity (pT73-Rab10) 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 ARRB1 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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
- ARRB1 in microglia, braak-0.09 (p 0.815) → -0.43 (p 0.253)receipt 4485
- ARRB1 in dopamine neurons, braak-0.36 (p 0.348) → -0.74 (p 0.023)receipt 4486
Swarm cases
receipt 4486: ARRB1 in dopamine neurons, braak
- power
- full sample -0.53 (p 0.022, n 18), 95% CI -0.80 to -0.09. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: -0.52 (p 0.027, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.58 (p 0.013, n 18). not the mix.
- skeptic
- leave-one-out range -0.63 to -0.47, sign flips 0; without severely affected donors -0.53 (p 0.022, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ARRB1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 4485: ARRB1 in microglia, braak
- power
- full sample -0.37 (p 0.132, n 18), 95% CI -0.71 to +0.12. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.37 (p 0.132, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.29 (p 0.246, n 18). could be the mix.
- skeptic
- leave-one-out range -0.54 to -0.30, sign flips 0; without severely affected donors -0.37 (p 0.132, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ARRB1 in microglia.
case closed: nothing better to follow up.
Receipts
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