Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.76 (overall 0.56) | 0.76 |
| 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 | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 60 Parkinson's papers of 236 | 0.46 |
| pathways Reactome | 2 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress GAK in a dopamine neuron, astrocyte and microglia tri-culture; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves LRRK2 kinase activity (pT73-Rab10) 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 GAK in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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 0.68; 2026-10-25 0.68; 2026-10-24 0.68; 2026-10-23 0.68.
Sealed predictions
- GAK in dopamine neurons, braak-0.58 (p 0.102) → -0.34 (p 0.375)receipt 0580
- GAK in dopamine neurons, resilience-0.22 (p 0.537) → -0.09 (p 0.722)receipt 0119
- GAK in dopamine neurons, braak+0.07 (p 0.640) → +0.06 (p 0.713)receipt 0118
Swarm cases
receipt 0580: GAK in dopamine neurons, braak
- power
- full sample -0.43 (p 0.074, n 18), 95% CI -0.75 to +0.04. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.46 (p 0.052, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.49 (p 0.037, n 18). not the mix.
- skeptic
- leave-one-out range -0.65 to -0.37, sign flips 0; without severely affected donors -0.43 (p 0.074, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GAK in dopamine neurons.
case closed: nothing better to follow up.
receipt 0119: GAK in dopamine neurons, resilience
- power
- full sample -0.17 (p 0.388, n 55), 95% CI -0.42 to +0.10. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: -0.12 (p 0.556, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.10 (p 0.599, n 55). could be the mix.
- skeptic
- leave-one-out range -0.27 to -0.10, sign flips 0; without severely affected donors -0.18 (p 0.361, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for GAK in dopamine neurons.
case closed: nothing better to follow up.
receipt 0118: GAK in dopamine neurons, braak
- power
- full sample +0.07 (p 0.511, n 84), 95% CI -0.14 to +0.28. the interval sits on zero: probably nothing there.
- confounder
- adjusted for age, sex and PMI: +0.11 (p 0.339, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: +0.06 (p 0.609, n 84). could be the mix.
- skeptic
- leave-one-out range +0.04 to +0.11, sign flips 0; without severely affected donors +0.09 (p 0.434, n 75). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GAK in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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