Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.35 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in megakaryocytes | 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 | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 5 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress ARPC4 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 ARPC4 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
- ARPC4 in microglia, braak+0.72 (p 0.028) → +0.37 (p 0.324)receipt 0910
- ARPC4 in dopamine neurons, braak+0.66 (p 0.054) → +0.30 (p 0.428)receipt 0911
Swarm cases
receipt 0911: ARPC4 in dopamine neurons, braak
- power
- full sample +0.51 (p 0.030, n 18), 95% CI +0.06 to +0.79. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.49 (p 0.040, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.49 (p 0.040, n 18). not the mix.
- skeptic
- leave-one-out range +0.45 to +0.63, sign flips 0; without severely affected donors +0.51 (p 0.030, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ARPC4 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0910: ARPC4 in microglia, braak
- power
- full sample +0.56 (p 0.016, n 18), 95% CI +0.12 to +0.81. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.55 (p 0.019, n 18). holds up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.56 (p 0.016, n 18). not the mix.
- skeptic
- leave-one-out range +0.50 to +0.68, sign flips 0; without severely affected donors +0.56 (p 0.016, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ARPC4 in microglia.
case closed: nothing better to follow up.
Receipts
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