Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.15 (overall 0.09) | 0.15 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: fosbretabulin, vincristine, verubulin +82 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 2 Parkinson's papers of 104 | 0.85 |
| pathways Reactome | 32 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress TUBA1B in a dopamine neuron, astrocyte and microglia tri-culture; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- 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 TUBA1B in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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
- TUBA1B in dopamine neurons, braak-0.05 (p 0.891) → +0.52 (p 0.151)receipt 2812
Swarm cases
receipt 2812: TUBA1B in dopamine neurons, braak
- power
- full sample +0.25 (p 0.319, n 18), 95% CI -0.25 to +0.64. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.20 (p 0.434, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.23 (p 0.351, n 18). could be the mix.
- skeptic
- leave-one-out range +0.18 to +0.43, sign flips 0; without severely affected donors +0.25 (p 0.319, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TUBA1B in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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