Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 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: brepocitinib, izencitinib, cerdulatinib +14 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 2 Parkinson's papers of 1,854 | 0.85 |
| pathways Reactome | 21 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress TYK2 in a dopamine neuron, astrocyte and microglia tri-culture; measure IL-1β and TNF release and surface HLA-DR 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
- IL-1β and TNF release and surface HLA-DR
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves IL-1β 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 TYK2 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; 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
- TYK2 in dopamine neurons, braak-0.27 (p 0.489) → -0.36 (p 0.347)receipt 8606
Swarm cases
receipt 8606: TYK2 in dopamine neurons, braak
- power
- full sample -0.31 (p 0.218, n 18), 95% CI -0.68 to +0.19. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.40 (p 0.101, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.36 (p 0.137, n 18). could be the mix.
- skeptic
- leave-one-out range -0.47 to -0.24, sign flips 0; without severely affected donors -0.31 (p 0.218, n 18). fragile.
- cell type
- strongest in OPCs: -0.71 (p 9.6e-4, n 18) vs -0.31 in dopamine neurons. proposing OPCs.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TYK2 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up TYK2 · OPCs · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) -0.05 p 0.859 (needs p < 2.5e-4)
Receipts
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