Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.74 (overall 0.78) | 0.74 |
| 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 | 316 Parkinson's papers of 633 | 0.24 |
| pathways Reactome | 1 pathway; mostly vesicle traffic | 1.00 |
Knock down and overexpress VPS35 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 VPS35 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 0.63; 2026-10-25 0.63; 2026-10-24 0.63; 2026-10-23 0.63.
Sealed predictions
- VPS35 in dopamine neurons, braak-0.06 (p 0.888) → -0.09 (p 0.825)receipt 0520
- VPS35 in dopamine neurons, resilience-0.16 (p 0.567) → -0.28 (p 0.330)receipt 0024
- VPS35 in dopamine neurons, braak+0.01 (p 0.953) → +0.06 (p 0.692)receipt 0023
In the sealed studies
- The lysosomal axis in dopamine neurons: did not hold
Swarm cases
receipt 0520: VPS35 in dopamine neurons, braak
- power
- full sample -0.09 (p 0.722, n 18), 95% CI -0.53 to +0.39. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.09 (p 0.735, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.14 (p 0.567, n 18). could be the mix.
- skeptic
- leave-one-out range -0.21 to +0.03, sign flips 2; without severely affected donors -0.09 (p 0.722, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for VPS35 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0024: VPS35 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: -0.24 (p 0.230, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.22 (p 0.256, n 55). could be the mix.
- skeptic
- leave-one-out range -0.21 to -0.10, sign flips 0; without severely affected donors -0.16 (p 0.432, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for VPS35 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0023: VPS35 in dopamine neurons, braak
- power
- full sample +0.02 (p 0.837, n 84), 95% CI -0.19 to +0.24. the interval sits on zero: probably nothing there.
- confounder
- adjusted for age, sex and PMI: +0.07 (p 0.552, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: -0.03 (p 0.767, n 84). could be the mix.
- skeptic
- leave-one-out range -0.00 to +0.05, sign flips 3; without severely affected donors +0.03 (p 0.766, n 75). fragile.
- cell type
- strongest in endothelial: -0.51 (p 7.2e-7, n 84) vs +0.02 in dopamine neurons. proposing endothelial.
- axis
- no measure beats "tracks Braak Lewy-body stage" for VPS35 in dopamine neurons.
follow-up registered; not confirmed in ventral tegmental area.
follow-up VPS35 · endothelial · braak: ventral tegmental area -0.28 p 0.012 (needs p < 0.010)
Receipts
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