Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.55 (overall 0.41) | 0.55 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: metformin hydrochloride, me-344, metformin | 1.00 |
| trials ClinicalTrials.gov | 4 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 2 Parkinson's papers of 166 | 0.85 |
| pathways Reactome | 3 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress MT-ND4 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 MT-ND4 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
- MT-ND4 in dopamine neurons, braak+0.50 (p 0.172) → -0.33 (p 0.389)receipt 0618
Swarm cases
receipt 0618: MT-ND4 in dopamine neurons, braak
- power
- full sample +0.09 (p 0.728, n 18), 95% CI -0.40 to +0.53. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.10 (p 0.696, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.10 (p 0.696, n 18). could be the mix.
- skeptic
- leave-one-out range -0.05 to +0.16, sign flips 4; without severely affected donors +0.09 (p 0.728, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for MT-ND4 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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