Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.38 (overall 0.23) | 0.38 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in esophageal apical cells | 0.75 |
| chemistry Open Targets | reachable by antibody | 0.45 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 4 Parkinson's papers of 23 | 0.79 |
| pathways Reactome | 1 pathway; mostly vesicle traffic | 1.00 |
Knock down and overexpress USP6NL 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 USP6NL 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
- USP6NL in dopamine neurons, braak+0.10 (p 0.803) → +0.19 (p 0.630)receipt 1837
- USP6NL in microglia, braak+0.01 (p 0.982) → +0.47 (p 0.197)receipt 1836
Swarm cases
receipt 1837: USP6NL in dopamine neurons, braak
- power
- full sample +0.28 (p 0.261, n 18), 95% CI -0.22 to +0.66. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.28 (p 0.265, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.29 (p 0.246, n 18). could be the mix.
- skeptic
- leave-one-out range +0.20 to +0.44, sign flips 0; without severely affected donors +0.28 (p 0.261, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for USP6NL in dopamine neurons.
case closed: nothing better to follow up.
receipt 1836: USP6NL in microglia, braak
- power
- full sample +0.26 (p 0.302, n 18), 95% CI -0.24 to +0.65. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.48 (p 0.046, n 18). holds up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.49 (p 0.040, n 18). not the mix.
- skeptic
- leave-one-out range +0.16 to +0.33, sign flips 0; without severely affected donors +0.26 (p 0.302, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for USP6NL in microglia.
case closed: nothing better to follow up.
Receipts
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