Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in brain inhibitory neurons (86 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: pregabalin, atagabalin, imagabalin +7 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 2 Parkinson's papers of 20 | 0.85 |
| pathways Reactome | 4 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress CACNG8 in dopamine neurons; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- 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 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 CACNG8 in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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
- CACNG8 in dopamine neurons, braak+0.16 (p 0.680) → -0.09 (p 0.825)receipt 13302
Swarm cases
receipt 13302: CACNG8 in dopamine neurons, braak
- power
- full sample -0.12 (p 0.646, n 18), 95% CI -0.55 to +0.37. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.09 (p 0.722, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.08 (p 0.761, n 18). could be the mix.
- skeptic
- leave-one-out range -0.29 to -0.01, sign flips 0; without severely affected donors -0.12 (p 0.646, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CACNG8 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
loading the receipts