Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.09 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in astrocytes (471 nCPM) | 1.00 |
| 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 | 5 Parkinson's papers of 909 | 0.76 |
| pathways Reactome | 11 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress GJA1 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 GJA1 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
- GJA1 in dopamine neurons, braak+0.69 (p 0.042) → +0.25 (p 0.508)receipt 3047
- GJA1 in astrocytes, braak+0.07 (p 0.855) → -0.51 (p 0.160)receipt 3046
Swarm cases
receipt 3047: GJA1 in dopamine neurons, braak
- power
- full sample +0.39 (p 0.114, n 18), 95% CI -0.10 to +0.72. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.32 (p 0.198, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.33 (p 0.182, n 18). could be the mix.
- skeptic
- leave-one-out range +0.32 to +0.56, sign flips 0; without severely affected donors +0.39 (p 0.114, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GJA1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 3046: GJA1 in astrocytes, braak
- power
- full sample -0.20 (p 0.418, n 18), 95% CI -0.61 to +0.29. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.16 (p 0.538, n 18). does not hold up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: -0.06 (p 0.820, n 18). could be the mix.
- skeptic
- leave-one-out range -0.36 to -0.10, sign flips 0; without severely affected donors -0.20 (p 0.418, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GJA1 in astrocytes.
case closed: nothing better to follow up.
Receipts
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