Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.94 (overall 0.85) | 0.94 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| trials ClinicalTrials.gov | 4 Parkinson's trials, 1 stopped | 0.80 |
| literature PubMed | 488 Parkinson's papers of 858 | 0.18 |
| pathways Reactome | 6 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress PRKN 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.
- 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 PRKN 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.
Earlier readings: 2026-10-26 0.66; 2026-10-25 0.66; 2026-10-24 0.66; 2026-10-23 0.53.
Sealed predictions
- PRKN in dopamine neurons, braak+0.64 (p 0.064) → -0.03 (p 0.946)receipt 0512
- PRKN in dopamine neurons, resilience+0.13 (p 0.614) → +0.30 (p 0.339)receipt 0011
- PRKN in dopamine neurons, braak-0.15 (p 0.337) → -0.27 (p 0.082)receipt 0010
In the sealed studies
- Mitochondrial quality control and Lewy stage: did not hold
Swarm cases
receipt 0512: PRKN in dopamine neurons, braak
- power
- full sample +0.24 (p 0.332, n 18), 95% CI -0.25 to +0.64. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.28 (p 0.258, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.37 (p 0.127, n 18). could be the mix.
- skeptic
- leave-one-out range +0.14 to +0.33, sign flips 0; without severely affected donors +0.24 (p 0.332, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PRKN in dopamine neurons.
case closed: nothing better to follow up.
receipt 0011: PRKN in dopamine neurons, resilience
- power
- full sample +0.23 (p 0.247, n 55), 95% CI -0.04 to +0.46. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: +0.26 (p 0.178, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: +0.24 (p 0.214, n 55). could be the mix.
- skeptic
- leave-one-out range +0.15 to +0.32, sign flips 0; without severely affected donors +0.26 (p 0.193, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for PRKN in dopamine neurons.
case closed: nothing better to follow up.
receipt 0010: PRKN in dopamine neurons, braak
- power
- full sample -0.24 (p 0.031, n 84), 95% CI -0.43 to -0.02. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for age, sex and PMI: -0.21 (p 0.056, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: -0.12 (p 0.282, n 84). could be the mix.
- skeptic
- leave-one-out range -0.26 to -0.21, sign flips 0; without severely affected donors -0.28 (p 0.014, n 75). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PRKN in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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