Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: fepixnebart | 0.81 |
| 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 | 21 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress TGFA 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 TGFA 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
- TGFA in dopamine neurons, braak+0.28 (p 0.473) → -0.27 (p 0.487)receipt 7468
Swarm cases
receipt 7468: TGFA in dopamine neurons, braak
- power
- full sample +0.06 (p 0.820, n 18), 95% CI -0.42 to +0.51. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.06 (p 0.800, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.12 (p 0.646, n 18). could be the mix.
- skeptic
- leave-one-out range -0.06 to +0.18, sign flips 4; without severely affected donors +0.06 (p 0.820, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TGFA in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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