Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 from other evidence | 0.00 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: iberdomide, pomalidomide, lenalidomide +1 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 2 Parkinson's papers of 399 | 0.85 |
| pathways Reactome | 10 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress CUL4A 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; existing compounds already reach the inhibition arm.
- 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 CUL4A 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
- CUL4A in dopamine neurons, braak-0.21 (p 0.581) → -0.43 (p 0.244)receipt 16322
Swarm cases
receipt 16322: CUL4A in dopamine neurons, braak
- power
- full sample -0.30 (p 0.228, n 18), 95% CI -0.67 to +0.20. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.27 (p 0.281, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.28 (p 0.254, n 18). could be the mix.
- skeptic
- leave-one-out range -0.44 to -0.22, sign flips 0; without severely affected donors -0.30 (p 0.228, n 18). fragile.
- cell type
- strongest in oligodendrocytes: +0.64 (p 0.0039, n 18) vs -0.30 in dopamine neurons. proposing oligodendrocytes.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CUL4A in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up CUL4A · oligodendrocytes · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) -0.15 p 0.594 (needs p < 1.4e-4)
Receipts
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