Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.88 (overall 0.83) | 0.88 |
| 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 | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 211 Parkinson's papers of 502 | 0.29 |
| pathways Reactome | 5 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress PLA2G6 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 PLA2G6 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 0.69; 2026-10-25 0.69; 2026-10-24 0.69; 2026-10-23 0.69.
Sealed predictions
- PLA2G6 in dopamine neurons, braak-0.11 (p 0.787) → -0.42 (p 0.258)receipt 0515
- PLA2G6 in dopamine neurons, resilience+0.09 (p 0.732) → +0.18 (p 0.570)receipt 0016
- PLA2G6 in dopamine neurons, braak-0.00 (p 0.998) → -0.13 (p 0.422)receipt 0015
Swarm cases
receipt 0515: PLA2G6 in dopamine neurons, braak
- power
- full sample -0.30 (p 0.225, n 18), 95% CI -0.67 to +0.19. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.33 (p 0.185, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.38 (p 0.123, n 18). could be the mix.
- skeptic
- leave-one-out range -0.45 to -0.21, sign flips 0; without severely affected donors -0.30 (p 0.225, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PLA2G6 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0016: PLA2G6 in dopamine neurons, resilience
- power
- full sample +0.14 (p 0.474, n 55), 95% CI -0.13 to +0.39. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: +0.15 (p 0.436, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: +0.16 (p 0.412, n 55). could be the mix.
- skeptic
- leave-one-out range +0.05 to +0.24, sign flips 0; without severely affected donors +0.14 (p 0.479, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for PLA2G6 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0015: PLA2G6 in dopamine neurons, braak
- power
- full sample -0.05 (p 0.620, n 84), 95% CI -0.27 to +0.16. the interval sits on zero: probably nothing there.
- confounder
- adjusted for age, sex and PMI: -0.05 (p 0.647, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: -0.08 (p 0.458, n 84). could be the mix.
- skeptic
- leave-one-out range -0.09 to -0.03, sign flips 0; without severely affected donors -0.07 (p 0.563, n 75). fragile.
- cell type
- strongest in microglia: +0.54 (p 1.3e-7, n 84) vs -0.05 in dopamine neurons. proposing microglia.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PLA2G6 in dopamine neurons.
follow-up confirmed in ventral tegmental area.
follow-up PLA2G6 · microglia · braak: ventral tegmental area +0.42 p 1.2e-4 (needs p < 0.050)
Receipts
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