Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 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: glpg-0259 | 0.90 |
| 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 | 3 pathways; mostly iron and oxidative stress | 0.80 |
Knock down and overexpress MAPKAPK5 in a dopamine neuron, astrocyte and microglia tri-culture; measure reactive oxygen species (CellROX) and lipid peroxidation and labile iron 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
- reactive oxygen species (CellROX) and lipid peroxidation and labile iron
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves reactive oxygen species (CellROX) 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 MAPKAPK5 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: reactive oxygen species (CellROX) and lipid peroxidation and labile iron; 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
- MAPKAPK5 in dopamine neurons, braak+0.35 (p 0.361) → -0.57 (p 0.109)receipt 16079
Swarm cases
receipt 16079: MAPKAPK5 in dopamine neurons, braak
- power
- full sample -0.01 (p 0.956, n 18), 95% CI -0.48 to +0.46. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.08 (p 0.761, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.17 (p 0.504, n 18). could be the mix.
- skeptic
- leave-one-out range -0.17 to +0.12, sign flips 6; without severely affected donors -0.01 (p 0.956, n 18). fragile.
- cell type
- strongest in astrocytes: -0.60 (p 0.0089, n 18) vs -0.01 in dopamine neurons. proposing astrocytes.
- axis
- no measure beats "tracks Braak Lewy-body stage" for MAPKAPK5 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up MAPKAPK5 · astrocytes · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) +0.02 p 0.929 (needs p < 1.4e-4)
Receipts
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