Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.04 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in oligodendrocytes (2117 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 | 8 Parkinson's papers of 115 | 0.71 |
| pathways Reactome | 5 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress DNM3 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.
- 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 DNM3 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
- DNM3 in dopamine neurons, braak-0.05 (p 0.891) → +0.61 (p 0.080)receipt 6205
- DNM3 in oligodendrocytes, braak+0.76 (p 0.018) → +0.17 (p 0.656)receipt 6204
Swarm cases
receipt 6205: DNM3 in dopamine neurons, braak
- power
- full sample +0.19 (p 0.460, n 18), 95% CI -0.31 to +0.60. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.22 (p 0.374, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.14 (p 0.573, n 18). could be the mix.
- skeptic
- leave-one-out range +0.08 to +0.30, sign flips 0; without severely affected donors +0.19 (p 0.460, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for DNM3 in dopamine neurons.
case closed: nothing better to follow up.
receipt 6204: DNM3 in oligodendrocytes, braak
- power
- full sample +0.46 (p 0.056, n 18), 95% CI -0.01 to +0.76. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.48 (p 0.044, n 18). holds up.
- composition
- oligodendrocytes share of nuclei vs axis +0.03 (p 0.915); controlling for it: +0.59 (p 0.011, n 18). not the mix.
- skeptic
- leave-one-out range +0.39 to +0.63, sign flips 0; without severely affected donors +0.46 (p 0.056, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for DNM3 in oligodendrocytes.
case closed: nothing better to follow up.
Receipts
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