Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.03 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in other brain neurons (43 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: gsk-690693 | 0.80 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 7 Parkinson's papers of 479 | 0.73 |
| pathways Reactome | 39 pathways; mostly mitochondrial quality control | 1.00 |
Knock down and overexpress PRKACA in dopamine neurons; measure PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub) 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
- PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub)
- 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 PINK1–parkin mitophagy flux (mt-Keima) 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 PRKACA in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: PINK1–parkin mitophagy flux (mt-Keima) and phospho-ubiquitin (pS65-Ub); 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
- PRKACA in dopamine neurons, braak+0.42 (p 0.258) → -0.63 (p 0.068)receipt 7016
Swarm cases
receipt 7016: PRKACA in dopamine neurons, braak
- power
- full sample -0.22 (p 0.389, n 18), 95% CI -0.62 to +0.28. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.32 (p 0.194, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.40 (p 0.097, n 18). could be the mix.
- skeptic
- leave-one-out range -0.31 to -0.11, sign flips 0; without severely affected donors -0.22 (p 0.389, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PRKACA in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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