Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.08 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in pdcs | 0.75 |
| chemistry Open Targets | compounds already reach it: cpg-52852, hydroxychloroquine, bazlitoran +9 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 8 Parkinson's papers of 5,756 | 0.71 |
| pathways Reactome | 11 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress TLR7 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; existing compounds already reach the inhibition arm.
- 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 TLR7 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
- TLR7 in dopamine neurons, braak+0.19 (p 0.618) → +0.28 (p 0.470)receipt 3335
- TLR7 in microglia, braak+0.53 (p 0.145) → +0.55 (p 0.122)receipt 3334
Swarm cases
receipt 3335: TLR7 in dopamine neurons, braak
- power
- full sample +0.23 (p 0.369, n 18), 95% CI -0.27 to +0.63. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.23 (p 0.369, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.18 (p 0.471, n 18). could be the mix.
- skeptic
- leave-one-out range +0.11 to +0.32, sign flips 0; without severely affected donors +0.23 (p 0.369, n 18). fragile.
- cell type
- strongest in microglia: +0.59 (p 0.0092, n 18) vs +0.23 in dopamine neurons. proposing microglia.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TLR7 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up TLR7 · microglia · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) +0.23 p 0.424 (needs p < 5.6e-4)
receipt 3334: TLR7 in microglia, braak
- power
- full sample +0.59 (p 0.0092, n 18), 95% CI +0.18 to +0.83. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.59 (p 0.0092, n 18). holds up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.69 (p 0.0015, n 18). not the mix.
- skeptic
- leave-one-out range +0.54 to +0.77, sign flips 0; without severely affected donors +0.59 (p 0.0092, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TLR7 in microglia.
case closed: nothing better to follow up.
Receipts
loading the receipts