Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.90 (overall 0.77) | 0.90 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: afegostat, afegostat tartrate | 0.90 |
| trials ClinicalTrials.gov | 43 Parkinson's trials, 3 stopped | 0.94 |
| literature PubMed | 741 Parkinson's papers of 1,042: well-trodden | 0.13 |
| pathways Reactome | 2 pathways; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress GBA1 in a dopamine neuron, astrocyte and microglia tri-culture; measure glucocerebrosidase (GCase) activity and LC3-II and p62 flux 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
- glucocerebrosidase (GCase) activity and LC3-II and p62 flux
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves glucocerebrosidase (GCase) activity 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 GBA1 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: glucocerebrosidase (GCase) activity and LC3-II and p62 flux; 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
- GBA1 in dopamine neurons, braakn/a → n/areceipt 0521
- GBA1 in dopamine neurons, resilience-0.09 (p 0.755) → +0.36 (p 0.179)receipt 0026
- GBA1 in dopamine neurons, braak-0.21 (p 0.177) → -0.07 (p 0.670)receipt 0025
In the sealed studies
- The lysosomal axis in dopamine neurons: did not hold
Swarm cases
receipt 0521: GBA1 in dopamine neurons, braak
- cell type
- GBA1 is not measured in dopamine neurons; looking elsewhere.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GBA1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0026: GBA1 in dopamine neurons, resilience
- power
- full sample +0.09 (p 0.643, n 55), 95% CI -0.18 to +0.35. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: +0.00 (p 1.000, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.02 (p 0.916, n 55). could be the mix.
- skeptic
- leave-one-out range +0.04 to +0.20, sign flips 0; without severely affected donors +0.01 (p 0.949, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for GBA1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0025: GBA1 in dopamine neurons, braak
- power
- full sample -0.13 (p 0.252, n 84), 95% CI -0.33 to +0.09. the interval sits on zero: probably nothing there.
- confounder
- adjusted for age, sex and PMI: -0.08 (p 0.447, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: -0.02 (p 0.888, n 84). could be the mix.
- skeptic
- leave-one-out range -0.16 to -0.10, sign flips 0; without severely affected donors -0.02 (p 0.854, n 75). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GBA1 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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