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 brain excitatory neurons (16 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: lithium carbonate, azd-1080, lithium citrate +1 | 1.00 |
| trials ClinicalTrials.gov | 5 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 2 Parkinson's papers of 117 | 0.85 |
| pathways Reactome | 6 pathways; mostly protein handling | 0.90 |
Knock down and overexpress GSK3A in dopamine neurons; measure proteasome activity and the load of ubiquitinated protein 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; existing compounds already reach the inhibition arm.
- Molecular readout
- proteasome activity and the load of ubiquitinated protein
- 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 proteasome activity 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 GSK3A in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: proteasome activity and the load of ubiquitinated protein; 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
- GSK3A in dopamine neurons, braak-0.07 (p 0.856) → -0.24 (p 0.533)receipt 6114
Swarm cases
receipt 6114: GSK3A in dopamine neurons, braak
- power
- full sample -0.14 (p 0.579, n 18), 95% CI -0.57 to +0.35. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.13 (p 0.609, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.20 (p 0.424, n 18). could be the mix.
- skeptic
- leave-one-out range -0.26 to -0.02, sign flips 0; without severely affected donors -0.14 (p 0.579, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GSK3A in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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