Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.03 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in enterocytes | 0.75 |
| chemistry Open Targets | compounds already reach it: apolizumab | 0.81 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 16 Parkinson's papers of 279 | 0.63 |
| pathways Reactome | 9 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress HLA-DRB5 in microglia; measure evoked dopamine release and dopamine transporter uptake 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
- evoked dopamine release and dopamine transporter uptake
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves evoked dopamine release 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 HLA-DRB5 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: evoked dopamine release and dopamine transporter uptake; 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
- HLA-DRB5 in microglia, braak-0.45 (p 0.227) → +0.11 (p 0.787)receipt 6533
- HLA-DRB5 in dopamine neurons, braak-0.42 (p 0.262) → +0.51 (p 0.160)receipt 6534
Swarm cases
receipt 6534: HLA-DRB5 in dopamine neurons, braak
- power
- full sample +0.01 (p 0.969, n 18), 95% CI -0.46 to +0.47. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.07 (p 0.794, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.04 (p 0.881, n 18). could be the mix.
- skeptic
- leave-one-out range -0.13 to +0.16, sign flips 8; without severely affected donors +0.01 (p 0.969, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HLA-DRB5 in dopamine neurons.
case closed: nothing better to follow up.
receipt 6533: HLA-DRB5 in microglia, braak
- power
- full sample -0.22 (p 0.384, n 18), 95% CI -0.62 to +0.28. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.13 (p 0.603, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.04 (p 0.881, n 18). could be the mix.
- skeptic
- leave-one-out range -0.38 to -0.12, sign flips 0; without severely affected donors -0.22 (p 0.384, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HLA-DRB5 in microglia.
case closed: nothing better to follow up.
Receipts
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