Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.11 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in cdc | 0.75 |
| chemistry Open Targets | compounds already reach it: lym-1, plovamer acetate, apolizumab | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 27 Parkinson's papers of 7,543 | 0.56 |
| pathways Reactome | 9 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress HLA-DRB1 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-DRB1 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-DRB1 in microglia, braak+0.07 (p 0.849) → +0.32 (p 0.407)receipt 2464
- HLA-DRB1 in dopamine neurons, braak-0.22 (p 0.567) → -0.26 (p 0.502)receipt 2465
In the sealed studies
- An antigen-presenting microglial response: did not hold
Swarm cases
receipt 2465: HLA-DRB1 in dopamine neurons, braak
- power
- full sample +0.02 (p 0.949, n 18), 95% CI -0.45 to +0.48. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.01 (p 0.956, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.01 (p 0.962, n 18). could be the mix.
- skeptic
- leave-one-out range -0.09 to +0.14, sign flips 8; without severely affected donors +0.02 (p 0.949, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HLA-DRB1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 2464: HLA-DRB1 in microglia, braak
- power
- full sample +0.06 (p 0.814, n 18), 95% CI -0.42 to +0.51. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.10 (p 0.702, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.01 (p 0.976, n 18). could be the mix.
- skeptic
- leave-one-out range -0.03 to +0.22, sign flips 5; without severely affected donors +0.06 (p 0.814, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HLA-DRB1 in microglia.
case closed: nothing better to follow up.
Receipts
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