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 müller glia | 0.75 |
| chemistry Open Targets | compounds already reach it: asg-5me, crolibulin, tisotumab vedotin +83 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 32 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress TUBB2B 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 TUBB2B 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
- TUBB2B in dopamine neurons, braak+0.63 (p 0.068) → -0.25 (p 0.524)receipt 4914
- TUBB2B in astrocytes, braak-0.24 (p 0.533) → -0.43 (p 0.243)receipt 4913
Swarm cases
receipt 4914: TUBB2B in dopamine neurons, braak
- power
- full sample +0.11 (p 0.652, n 18), 95% CI -0.37 to +0.55. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.07 (p 0.787, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.08 (p 0.741, n 18). could be the mix.
- skeptic
- leave-one-out range +0.03 to +0.26, sign flips 0; without severely affected donors +0.11 (p 0.652, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TUBB2B in dopamine neurons.
case closed: nothing better to follow up.
receipt 4913: TUBB2B in astrocytes, braak
- power
- full sample -0.39 (p 0.105, n 18), 95% CI -0.73 to +0.09. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.38 (p 0.116, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.35 (p 0.156, n 18). could be the mix.
- skeptic
- leave-one-out range -0.51 to -0.31, sign flips 0; without severely affected donors -0.39 (p 0.105, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TUBB2B in astrocytes.
case closed: nothing better to follow up.
Receipts
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