Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.74 (overall 0.47) | 0.74 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in kupffer cells | 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 | 56 Parkinson's papers of 1,104 | 0.47 |
| pathways Reactome | 8 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress CTSB 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 CTSB 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
- CTSB in dopamine neurons, braak+0.24 (p 0.529) → -0.17 (p 0.670)receipt 0283
- CTSB in microglia, braak+0.21 (p 0.586) → -0.63 (p 0.068)receipt 0282
In the sealed studies
- The lysosomal axis in dopamine neurons: did not hold
Swarm cases
receipt 0283: CTSB in dopamine neurons, braak
- power
- full sample -0.13 (p 0.597, n 18), 95% CI -0.57 to +0.36. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.14 (p 0.573, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.19 (p 0.460, n 18). could be the mix.
- skeptic
- leave-one-out range -0.28 to -0.03, sign flips 0; without severely affected donors -0.13 (p 0.597, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CTSB in dopamine neurons.
case closed: nothing better to follow up.
receipt 0282: CTSB in microglia, braak
- power
- full sample -0.29 (p 0.243, n 18), 95% CI -0.67 to +0.20. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.26 (p 0.298, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.31 (p 0.207, n 18). could be the mix.
- skeptic
- leave-one-out range -0.48 to -0.19, sign flips 0; without severely affected donors -0.29 (p 0.243, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CTSB in microglia.
case closed: nothing better to follow up.
Receipts
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