Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.40 (overall 0.24) | 0.40 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 141 | 0.91 |
| pathways Reactome | 3 pathways; mostly protein handling | 0.90 |
Knock down and overexpress CNOT1 in a dopamine neuron, astrocyte and microglia tri-culture; measure proteasome activity and the load of ubiquitinated protein 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
- proteasome activity and the load of ubiquitinated protein
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves proteasome 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 CNOT1 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: proteasome activity and the load of ubiquitinated protein; 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
- CNOT1 in dopamine neurons, braak+0.30 (p 0.428) → -0.13 (p 0.739)receipt 1742
Swarm cases
receipt 1742: CNOT1 in dopamine neurons, braak
- power
- full sample +0.11 (p 0.658, n 18), 95% CI -0.37 to +0.55. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.19 (p 0.450, 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 0.504, n 18). could be the mix.
- skeptic
- leave-one-out range +0.01 to +0.25, sign flips 0; without severely affected donors +0.11 (p 0.658, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CNOT1 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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