Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.05 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in neutrophils | 0.75 |
| chemistry Open Targets | compounds already reach it: brontictuzumab | 0.81 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 20 Parkinson's papers of 10,041 | 0.60 |
| pathways Reactome | 24 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress NOTCH1 in astrocytes; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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; existing compounds already reach the inhibition arm.
- Molecular readout
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- 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 NOTCH1 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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
- NOTCH1 in dopamine neurons, braak-0.32 (p 0.400) → -0.47 (p 0.204)receipt 4885
- NOTCH1 in astrocytes, braak-0.52 (p 0.150) → -0.21 (p 0.589)receipt 4884
Swarm cases
receipt 4885: NOTCH1 in dopamine neurons, braak
- power
- full sample -0.52 (p 0.027, n 18), 95% CI -0.79 to -0.07. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: -0.48 (p 0.045, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.59 (p 0.0092, n 18). not the mix.
- skeptic
- leave-one-out range -0.66 to -0.46, sign flips 0; without severely affected donors -0.52 (p 0.027, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for NOTCH1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 4884: NOTCH1 in astrocytes, braak
- power
- full sample -0.28 (p 0.254, n 18), 95% CI -0.66 to +0.21. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.31 (p 0.211, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.23 (p 0.355, n 18). could be the mix.
- skeptic
- leave-one-out range -0.41 to -0.19, sign flips 0; without severely affected donors -0.28 (p 0.254, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for NOTCH1 in astrocytes.
case closed: nothing better to follow up.
Receipts
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