Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.60 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including brain inhibitory neurons; strongest in choroid plexus epithelial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: me-344, metformin, metformin hydrochloride | 1.00 |
| trials ClinicalTrials.gov | 4 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 12 Parkinson's papers of 234 | 0.66 |
| pathways Reactome | 3 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress NDUFS1 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; existing compounds already reach the inhibition arm.
- 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 NDUFS1 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.
Earlier readings: 2026-10-26 0.59; 2026-10-25 0.59; 2026-10-24 0.59; 2026-10-23 0.59.
Sealed predictions
- NDUFS1 in dopamine neurons, braak-0.37 (p 0.323) → +0.79 (p 0.011)receipt 0559
- NDUFS1 in dopamine neurons, resilience+0.20 (p 0.485) → +0.37 (p 0.182)receipt 0086
- NDUFS1 in dopamine neurons, braak-0.06 (p 0.721) → -0.39 (p 0.010)receipt 0085
Swarm cases
receipt 0559: NDUFS1 in dopamine neurons, braak
- power
- full sample +0.27 (p 0.277, n 18), 95% CI -0.22 to +0.65. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.29 (p 0.239, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.35 (p 0.150, n 18). could be the mix.
- skeptic
- leave-one-out range +0.17 to +0.40, sign flips 0; without severely affected donors +0.27 (p 0.277, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for NDUFS1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0086: NDUFS1 in dopamine neurons, resilience
- power
- full sample +0.22 (p 0.265, n 55), 95% CI -0.05 to +0.46. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: +0.23 (p 0.239, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: +0.21 (p 0.283, n 55). could be the mix.
- skeptic
- leave-one-out range +0.15 to +0.31, sign flips 0; without severely affected donors +0.19 (p 0.334, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for NDUFS1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0085: NDUFS1 in dopamine neurons, braak
- power
- full sample -0.21 (p 0.057, n 84), 95% CI -0.41 to +0.01. the interval sits on zero: probably nothing there.
- confounder
- adjusted for age, sex and PMI: -0.19 (p 0.078, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: -0.05 (p 0.639, n 84). could be the mix.
- skeptic
- leave-one-out range -0.24 to -0.18, sign flips 0; without severely affected donors -0.18 (p 0.125, n 75). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for NDUFS1 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
loading the receipts