Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | group enriched in microglia (552 nCPM) | 1.00 |
| chemistry Open Targets | a small-molecule pocket: cd24fc | 0.60 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 6 Parkinson's papers of 414 | 0.74 |
| pathways Reactome | 9 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress HSPA1B in microglia; measure PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub) 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
- PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub)
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves PINK1–parkin mitophagy flux (mt-Keima) 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 HSPA1B in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub); 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
- HSPA1B in dopamine neurons, braak+0.14 (p 0.714) → +0.02 (p 0.965)receipt 8009
- HSPA1B in microglia, braak+0.31 (p 0.414) → -0.24 (p 0.533)receipt 8008
Swarm cases
receipt 8009: HSPA1B in dopamine neurons, braak
- power
- full sample +0.03 (p 0.922, n 18), 95% CI -0.45 to +0.49. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.11 (p 0.677, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.23 (p 0.360, n 18). could be the mix.
- skeptic
- leave-one-out range -0.07 to +0.19, sign flips 7; without severely affected donors +0.03 (p 0.922, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HSPA1B in dopamine neurons.
case closed: nothing better to follow up.
receipt 8008: HSPA1B in microglia, braak
- power
- full sample -0.10 (p 0.696, n 18), 95% CI -0.54 to +0.39. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.14 (p 0.579, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.07 (p 0.774, n 18). could be the mix.
- skeptic
- leave-one-out range -0.21 to +0.04, sign flips 2; without severely affected donors -0.10 (p 0.696, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HSPA1B in microglia.
case closed: nothing better to follow up.
Receipts
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