Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.24 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including other brain neurons; strongest in corticotrophs | 0.75 |
| chemistry Open Targets | compounds already reach it: pf-04991532, azd-1656, ly-2608204 +3 | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 1,739 | 0.91 |
| pathways Reactome | 6 pathways; mostly iron and oxidative stress | 0.80 |
Knock down and overexpress GCK in dopamine neurons; measure reactive oxygen species (CellROX) and lipid peroxidation and labile iron and survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils.
- Cell type
- dopamine neurons
- Direction
- Both arms: public data does not say which way helps.
- Molecular readout
- reactive oxygen species (CellROX) and lipid peroxidation and labile iron
- Functional readout
- survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils
- 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 GCK in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: reactive oxygen species (CellROX) and lipid peroxidation and labile iron; survival of TH-positive neurons and phospho-α-synuclein (pS129) inclusions after seeding with α-synuclein fibrils. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- GCK in dopamine neurons, braak-0.41 (p 0.273) → -0.26 (p 0.493)receipt 1778
Swarm cases
receipt 1778: GCK in dopamine neurons, braak
- power
- full sample -0.40 (p 0.099, n 18), 95% CI -0.73 to +0.08. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.40 (p 0.099, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.63 (p 0.0049, n 18). not the mix.
- skeptic
- leave-one-out range -0.53 to -0.32, sign flips 0; without severely affected donors -0.40 (p 0.099, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GCK in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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