Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.08 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in oligodendrocytes (184 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: denintuzumab mafodotin, epothilone d, imgn-388 +83 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 4 Parkinson's papers of 141 | 0.79 |
| pathways Reactome | 38 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress TUBB4A in oligodendrocytes; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position and α-synuclein uptake and myelin basic protein output under oxidative stress.
- Cell type
- oligodendrocytes
- 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 myelin basic protein output under oxidative stress
- 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 TUBB4A in iPSC-derived oligodendrocytes; n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; α-synuclein uptake and myelin basic protein output under oxidative stress. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- TUBB4A in dopamine neurons, braak+0.03 (p 0.946) → -0.26 (p 0.493)receipt 3391
- TUBB4A in oligodendrocytes, braak+0.23 (p 0.549) → -0.22 (p 0.576)receipt 3390
Swarm cases
receipt 3391: TUBB4A in dopamine neurons, braak
- power
- full sample -0.02 (p 0.935, n 18), 95% CI -0.48 to +0.45. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.01 (p 0.983, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.06 (p 0.820, n 18). could be the mix.
- skeptic
- leave-one-out range -0.16 to +0.06, sign flips 8; without severely affected donors -0.02 (p 0.935, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TUBB4A in dopamine neurons.
case closed: nothing better to follow up.
receipt 3390: TUBB4A in oligodendrocytes, braak
- power
- full sample +0.01 (p 0.969, n 18), 95% CI -0.46 to +0.47. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.01 (p 0.969, n 18). does not hold up.
- composition
- oligodendrocytes share of nuclei vs axis +0.03 (p 0.915); controlling for it: -0.01 (p 0.976, n 18). could be the mix.
- skeptic
- leave-one-out range -0.09 to +0.14, sign flips 6; without severely affected donors +0.01 (p 0.969, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TUBB4A in oligodendrocytes.
case closed: nothing better to follow up.
Receipts
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