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 | 13 Parkinson's trials, 1 stopped | 0.94 |
| literature PubMed | 2,211 Parkinson's papers of 6,216: well-trodden | 0.00 |
| pathways Reactome | 2 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress PINK1 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 PINK1 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 0.64; 2026-10-25 0.64; 2026-10-24 0.64; 2026-10-23 0.51.
Sealed predictions
- PINK1 in dopamine neurons, braak-0.42 (p 0.006) → -0.34 (p 0.030)held
- PINK1 in dopamine neurons, braak-0.02 (p 0.964) → -0.34 (p 0.378)receipt 0514
- PINK1 in dopamine neurons, resilience-0.41 (p 0.116) → +0.17 (p 0.583)receipt 0013
In the sealed studies
- Mitochondrial quality control and Lewy stage: did not hold
Swarm cases
receipt 0514: PINK1 in dopamine neurons, braak
- power
- full sample -0.29 (p 0.246, n 18), 95% CI -0.67 to +0.21. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.34 (p 0.167, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.34 (p 0.164, n 18). could be the mix.
- skeptic
- leave-one-out range -0.39 to -0.18, sign flips 0; without severely affected donors -0.29 (p 0.246, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PINK1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0013: PINK1 in dopamine neurons, resilience
- power
- full sample -0.14 (p 0.487, n 55), 95% CI -0.39 to +0.13. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: -0.11 (p 0.584, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.33 (p 0.096, n 55). could be the mix.
- skeptic
- leave-one-out range -0.23 to -0.06, sign flips 0; without severely affected donors -0.19 (p 0.347, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- braak beats resilience for PINK1 in dopamine neurons: -0.38 (p 4.1e-4, n 84). proposing braak.
case closed: every proposal failed a challenge.
Receipts
loading the receipts