Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.38 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including oligodendrocyte progenitor cells; strongest in retinal horizontal cells | 0.75 |
| chemistry Open Targets | compounds already reach it: osavampator, cx1739, mibampator +10 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 1 stopped | 0.60 |
| literature PubMed | 3 Parkinson's papers of 132 | 0.82 |
| pathways Reactome | 5 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress GRIA4 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 GRIA4 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
- GRIA4 in oligodendrocytes, braak+0.03 (p 0.929) → +0.24 (p 0.533)receipt 0715
- GRIA4 in dopamine neurons, braak-0.19 (p 0.623) → +0.37 (p 0.334)receipt 0716
Swarm cases
receipt 0716: GRIA4 in dopamine neurons, braak
- power
- full sample +0.12 (p 0.640, n 18), 95% CI -0.37 to +0.55. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.20 (p 0.434, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.18 (p 0.487, n 18). could be the mix.
- skeptic
- leave-one-out range -0.00 to +0.28, sign flips 1; without severely affected donors +0.12 (p 0.640, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GRIA4 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0715: GRIA4 in oligodendrocytes, braak
- power
- full sample +0.12 (p 0.633, n 18), 95% CI -0.37 to +0.56. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.19 (p 0.444, n 18). does not hold up.
- composition
- oligodendrocytes share of nuclei vs axis +0.03 (p 0.915); controlling for it: +0.19 (p 0.439, n 18). could be the mix.
- skeptic
- leave-one-out range -0.01 to +0.23, sign flips 1; without severely affected donors +0.12 (p 0.633, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GRIA4 in oligodendrocytes.
case closed: nothing better to follow up.
Receipts
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