Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: abc-294640 | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 5 Parkinson's papers of 588 | 0.76 |
| pathways Reactome | 1 pathway; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress SPHK2 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; existing compounds already reach the inhibition arm.
- 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 SPHK2 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.
Sealed predictions
- SPHK2 in dopamine neurons, braak-0.52 (p 0.149) → -0.35 (p 0.361)receipt 7194
Swarm cases
receipt 7194: SPHK2 in dopamine neurons, braak
- power
- full sample -0.41 (p 0.089, n 18), 95% CI -0.74 to +0.07. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.41 (p 0.095, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.51 (p 0.029, n 18). not the mix.
- skeptic
- leave-one-out range -0.52 to -0.34, sign flips 0; without severely affected donors -0.41 (p 0.089, n 18). robust.
- cell type
- strongest in microglia: -0.78 (p 1.4e-4, n 18) vs -0.41 in dopamine neurons. proposing microglia.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SPHK2 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up SPHK2 · microglia · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) +0.13 p 0.657 (needs p < 2.9e-4)
Receipts
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