Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.26 (overall 0.16) | 0.26 |
| cell type Human Protein Atlas | cell type enhanced, including brain excitatory neurons; strongest in somatotrophs | 0.75 |
| 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 | 1 Parkinson's papers of 33 | 0.91 |
| pathways Reactome | 2 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress MICU3 in dopamine neurons; measure PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub) and survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils.
- Cell type
- dopamine neurons
- 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
- survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils
- 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 MICU3 in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub); survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- MICU3 in dopamine neurons, braak-0.07 (p 0.855) → +0.61 (p 0.078)receipt 2159
Swarm cases
receipt 2159: MICU3 in dopamine neurons, braak
- power
- full sample +0.20 (p 0.434, n 18), 95% CI -0.30 to +0.61. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.21 (p 0.408, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.15 (p 0.555, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.30, sign flips 0; without severely affected donors +0.20 (p 0.434, n 18). fragile.
- cell type
- strongest in oligodendrocytes: +0.65 (p 0.0036, n 18) vs +0.20 in dopamine neurons. proposing oligodendrocytes.
- axis
- no measure beats "tracks Braak Lewy-body stage" for MICU3 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up MICU3 · oligodendrocytes · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) -0.20 p 0.477 (needs p < 7.4e-4)
Receipts
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