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 in microglia (1396 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 | 14 Parkinson's papers of 827 | 0.64 |
| pathways Reactome | 11 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress HSPA1A 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 HSPA1A 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
- HSPA1A in microglia, braak+0.26 (p 0.498) → -0.58 (p 0.102)receipt 3115
- HSPA1A in dopamine neurons, braak+0.26 (p 0.502) → +0.13 (p 0.739)receipt 3116
Swarm cases
receipt 3116: HSPA1A in dopamine neurons, braak
- power
- full sample +0.16 (p 0.515, n 18), 95% CI -0.33 to +0.59. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.17 (p 0.509, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.25 (p 0.310, n 18). could be the mix.
- skeptic
- leave-one-out range +0.06 to +0.27, sign flips 0; without severely affected donors +0.16 (p 0.515, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HSPA1A in dopamine neurons.
case closed: nothing better to follow up.
receipt 3115: HSPA1A in microglia, braak
- power
- full sample -0.02 (p 0.942, n 18), 95% CI -0.48 to +0.45. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.01 (p 0.962, 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 -0.12 to +0.13, sign flips 5; without severely affected donors -0.02 (p 0.942, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HSPA1A in microglia.
case closed: nothing better to follow up.
Receipts
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