Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.63 from other evidence | 0.00 |
| cell type Human Protein Atlas | group enriched, including brain inhibitory neurons; strongest in retinal amacrine cells | 0.75 |
| chemistry Open Targets | compounds already reach it: fenoldopam mesylate, minaprine hydrochloride, ecopipam +12 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | 67 Parkinson's papers of 944 | 0.45 |
| pathways Reactome | 2 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress DRD1 in dopamine neurons; measure evoked dopamine release and dopamine transporter uptake 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
- evoked dopamine release and dopamine transporter uptake
- 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 evoked dopamine release 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 DRD1 in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: evoked dopamine release and dopamine transporter uptake; 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
- DRD1 in dopamine neurons, braak+0.51 (p 5.9e-4) → +0.39 (p 0.012)held
- DRD1 in dopamine neurons, braak+0.12 (p 0.756) → -0.45 (p 0.230)receipt 0538
- DRD1 in dopamine neurons, resilience-0.28 (p 0.394) → -0.33 (p 0.186)receipt 0051
Swarm cases
receipt 0538: DRD1 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: -0.25 (p 0.315, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.32 (p 0.194, n 18). could be the mix.
- skeptic
- leave-one-out range -0.37 to -0.13, 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 DRD1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0051: DRD1 in dopamine neurons, resilience
- power
- full sample -0.31 (p 0.110, n 55), 95% CI -0.53 to -0.05. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for age, sex and PMI: -0.33 (p 0.092, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.30 (p 0.125, n 55). could be the mix.
- skeptic
- leave-one-out range -0.43 to -0.26, sign flips 0; without severely affected donors -0.23 (p 0.263, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- braak beats resilience for DRD1 in dopamine neurons: +0.47 (p 8.2e-6, n 84). proposing braak.
case closed: every proposal failed a challenge.
Receipts
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