Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.46 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including other brain neurons; strongest in choroid plexus epithelial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: pf-05175157, olumacostat glasaretil, firsocostat +1 | 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 | 6 pathways; mostly energy | 0.60 |
Knock down and overexpress ACACA in dopamine neurons; measure oxygen consumption rate and ATP output 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
- oxygen consumption rate and ATP output
- 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 oxygen consumption rate 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 ACACA in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: oxygen consumption rate and ATP output; 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
- ACACA in dopamine neurons, braak-0.09 (p 0.820) → +0.43 (p 0.243)receipt 0394
Swarm cases
receipt 0394: ACACA in dopamine neurons, braak
- power
- full sample +0.06 (p 0.814, n 18), 95% CI -0.42 to +0.51. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.03 (p 0.908, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.10 (p 0.702, n 18). could be the mix.
- skeptic
- leave-one-out range -0.07 to +0.20, sign flips 2; without severely affected donors +0.06 (p 0.814, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ACACA in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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