Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.16 (overall 0.11) | 0.16 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in vascular endothelial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: cenerimod, amiselimod hydrochloride, amiselimod +11 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 9 Parkinson's papers of 1,170 | 0.70 |
| pathways Reactome | 3 pathways; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress S1PR1 in astrocytes; measure glucocerebrosidase (GCase) activity and LC3-II and p62 flux and α-synuclein uptake and degradation, and dopamine neuron survival in co-culture.
- Cell type
- astrocytes
- Direction
- Both arms: public data does not say which way helps.
- Molecular readout
- glucocerebrosidase (GCase) activity and LC3-II and p62 flux
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- 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 S1PR1 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: glucocerebrosidase (GCase) activity and LC3-II and p62 flux; α-synuclein uptake and degradation, and dopamine neuron survival in co-culture. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- S1PR1 in astrocytes, braak+0.16 (p 0.685) → +0.23 (p 0.554)receipt 2513
- S1PR1 in dopamine neurons, braak+0.37 (p 0.334) → -0.46 (p 0.212)receipt 2514
Swarm cases
receipt 2514: S1PR1 in dopamine neurons, braak
- power
- full sample -0.08 (p 0.761, n 18), 95% CI -0.53 to +0.40. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.15 (p 0.549, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.17 (p 0.498, n 18). could be the mix.
- skeptic
- leave-one-out range -0.20 to +0.00, sign flips 1; without severely affected donors -0.08 (p 0.761, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for S1PR1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 2513: S1PR1 in astrocytes, braak
- power
- full sample +0.09 (p 0.715, n 18), 95% CI -0.39 to +0.54. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.16 (p 0.538, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.17 (p 0.504, n 18). could be the mix.
- skeptic
- leave-one-out range -0.03 to +0.20, sign flips 3; without severely affected donors +0.09 (p 0.715, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for S1PR1 in astrocytes.
case closed: nothing better to follow up.
Receipts
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