Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.52 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: metformin hydrochloride, metformin, me-344 | 1.00 |
| trials ClinicalTrials.gov | 4 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 1 Parkinson's papers of 35 | 0.91 |
| pathways Reactome | 2 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress NDUFB4 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 NDUFB4 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
- NDUFB4 in dopamine neurons, braak+0.40 (p 0.285) → +0.77 (p 0.015)receipt 0208
Swarm cases
receipt 0208: NDUFB4 in dopamine neurons, braak
- power
- full sample +0.62 (p 0.0064, n 18), 95% CI +0.21 to +0.84. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.58 (p 0.013, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.62 (p 0.0062, n 18). not the mix.
- skeptic
- leave-one-out range +0.57 to +0.77, sign flips 0; without severely affected donors +0.62 (p 0.0064, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for NDUFB4 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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