Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| 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 | 45 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress POLR2D in a dopamine neuron, astrocyte and microglia tri-culture; measure PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub) and dopamine neuron survival after α-synuclein fibril challenge.
- Cell type
- a dopamine neuron, astrocyte and microglia tri-culture
- Direction
- Both arms: public data does not say which way helps.
- Molecular readout
- PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub)
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- 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 POLR2D in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub); dopamine neuron survival after α-synuclein fibril challenge. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- POLR2D in dopamine neurons, braak+0.18 (p 0.638) → +0.01 (p 0.982)receipt 11233
Swarm cases
receipt 11233: POLR2D in dopamine neurons, braak
- power
- full sample +0.21 (p 0.403, n 18), 95% CI -0.28 to +0.62. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.28 (p 0.265, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.33 (p 0.182, n 18). could be the mix.
- skeptic
- leave-one-out range +0.12 to +0.38, sign flips 0; without severely affected donors +0.21 (p 0.403, n 18). fragile.
- cell type
- strongest in astrocytes: -0.71 (p 8.7e-4, n 18) vs +0.21 in dopamine neurons. proposing astrocytes.
- axis
- no measure beats "tracks Braak Lewy-body stage" for POLR2D in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up POLR2D · astrocytes · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) -0.38 p 0.183 (needs p < 1.9e-4)
Receipts
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