Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in microglia (57 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: lirentelimab | 0.81 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 1 pathway; mostly immune signalling | 0.90 |
Knock down and overexpress SIGLEC8 in microglia; measure IL-1β and TNF release and surface HLA-DR 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
- IL-1β and TNF release and surface HLA-DR
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves IL-1β 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 SIGLEC8 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; 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
- SIGLEC8 in dopamine neurons, braak-0.73 (p 0.026) → -0.46 (p 0.209)receipt 13789
- SIGLEC8 in microglia, braak+0.10 (p 0.795) → +0.04 (p 0.924)receipt 13788
Swarm cases
receipt 13789: SIGLEC8 in dopamine neurons, braak
- power
- full sample -0.55 (p 0.018, n 18), 95% CI -0.81 to -0.11. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: -0.55 (p 0.018, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.58 (p 0.012, n 18). not the mix.
- skeptic
- leave-one-out range -0.62 to -0.50, sign flips 0; without severely affected donors -0.55 (p 0.018, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SIGLEC8 in dopamine neurons.
case closed: nothing better to follow up.
receipt 13788: SIGLEC8 in microglia, braak
- power
- full sample -0.01 (p 0.976, n 18), 95% CI -0.47 to +0.46. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.04 (p 0.874, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.23 (p 0.360, n 18). could be the mix.
- skeptic
- leave-one-out range -0.13 to +0.10, sign flips 11; without severely affected donors -0.01 (p 0.976, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SIGLEC8 in microglia.
case closed: nothing better to follow up.
Receipts
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