Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.45 (overall 0.28) | 0.45 |
| cell type Human Protein Atlas | cell type enhanced, including astrocytes; strongest in late spermatids | 0.75 |
| 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 | 10 Parkinson's papers of 726 | 0.69 |
| pathways Reactome | 3 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress WNT3 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.
- 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 WNT3 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
- WNT3 in astrocytes, braak-0.68 (p 0.042) → -0.38 (p 0.316)receipt 1380
- WNT3 in dopamine neurons, braak-0.21 (p 0.581) → -0.37 (p 0.323)receipt 1381
Swarm cases
receipt 1381: WNT3 in dopamine neurons, braak
- power
- full sample -0.24 (p 0.341, n 18), 95% CI -0.63 to +0.26. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.26 (p 0.289, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.40 (p 0.099, n 18). could be the mix.
- skeptic
- leave-one-out range -0.39 to -0.15, sign flips 0; without severely affected donors -0.24 (p 0.341, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for WNT3 in dopamine neurons.
case closed: nothing better to follow up.
receipt 1380: WNT3 in astrocytes, braak
- power
- full sample -0.36 (p 0.137, n 18), 95% CI -0.71 to +0.12. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.38 (p 0.120, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.38 (p 0.120, n 18). could be the mix.
- skeptic
- leave-one-out range -0.49 to -0.27, sign flips 0; without severely affected donors -0.36 (p 0.137, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for WNT3 in astrocytes.
case closed: nothing better to follow up.
Receipts
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