Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.61 from other evidence | 0.00 |
| cell type Human Protein Atlas | group enriched in brain inhibitory neurons (15 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: regadenoson, uk432097, sonedenoson +24 | 1.00 |
| trials ClinicalTrials.gov | 6 Parkinson's trials, 1 stopped | 0.87 |
| literature PubMed | 21 Parkinson's papers of 471 | 0.59 |
| pathways Reactome | 4 pathways; mostly energy | 0.60 |
Knock down and overexpress ADORA2A 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 ADORA2A 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.
Earlier readings: 2026-10-26 0.55; 2026-10-25 0.55; 2026-10-24 0.55; 2026-10-23 0.55.
Sealed predictions
- ADORA2A in dopamine neurons, braak-0.51 (p 0.163) → -0.01 (p 0.982)receipt 0550
- ADORA2A in dopamine neurons, braak-0.32 (p 0.036) → -0.03 (p 0.853)receipt 0072
- ADORA2A in dopamine neurons, resilience-0.33 (p 0.216) → +0.37 (p 0.205)receipt 0073
Swarm cases
receipt 0550: ADORA2A in dopamine neurons, braak
- power
- full sample -0.22 (p 0.384, n 18), 95% CI -0.62 to +0.28. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.24 (p 0.328, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.46 (p 0.057, n 18). could be the mix.
- skeptic
- leave-one-out range -0.34 to -0.12, sign flips 0; without severely affected donors -0.22 (p 0.384, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ADORA2A in dopamine neurons.
case closed: nothing better to follow up.
receipt 0073: ADORA2A in dopamine neurons, resilience
- power
- full sample -0.05 (p 0.784, n 55), 95% CI -0.31 to +0.21. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: -0.03 (p 0.883, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.06 (p 0.752, n 55). could be the mix.
- skeptic
- leave-one-out range -0.16 to +0.02, sign flips 3; without severely affected donors -0.03 (p 0.867, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for ADORA2A in dopamine neurons.
case closed: nothing better to follow up.
receipt 0072: ADORA2A in dopamine neurons, braak
- power
- full sample -0.17 (p 0.129, n 84), 95% CI -0.37 to +0.05. the interval sits on zero: probably nothing there.
- confounder
- adjusted for age, sex and PMI: -0.17 (p 0.113, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: -0.11 (p 0.333, n 84). could be the mix.
- skeptic
- leave-one-out range -0.20 to -0.14, sign flips 0; without severely affected donors -0.20 (p 0.087, n 75). robust.
- cell type
- strongest in microglia: -0.43 (p 5.0e-5, n 84) vs -0.17 in dopamine neurons. proposing microglia.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ADORA2A in dopamine neurons.
follow-up registered; not confirmed in ventral tegmental area.
follow-up ADORA2A · microglia · braak: ventral tegmental area -0.24 p 0.030 (needs p < 0.0042)
Receipts
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