Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.70 from other evidence | 0.00 |
| cell type Human Protein Atlas | group enriched in brain inhibitory neurons (260 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: ralfinamide, amantadine hydrochloride, av-101 +28 | 1.00 |
| trials ClinicalTrials.gov | 49 Parkinson's trials, 8 stopped | 0.87 |
| literature PubMed | 11 Parkinson's papers of 468 | 0.67 |
| pathways Reactome | 9 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress GRIN1 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 GRIN1 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 0.62; 2026-10-25 0.62; 2026-10-24 0.62; 2026-10-23 0.62.
Sealed predictions
- GRIN1 in dopamine neurons, braak-0.33 (p 0.386) → -0.12 (p 0.768)receipt 0524
- GRIN1 in dopamine neurons, resiliencen/a → n/areceipt 0030
- GRIN1 in dopamine neurons, braakn/a → n/areceipt 0029
Swarm cases
receipt 0524: GRIN1 in dopamine neurons, braak
- power
- full sample -0.22 (p 0.374, n 18), 95% CI -0.62 to +0.27. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.23 (p 0.365, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.45 (p 0.063, n 18). could be the mix.
- skeptic
- leave-one-out range -0.32 to -0.12, sign flips 0; without severely affected donors -0.22 (p 0.374, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GRIN1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0030: GRIN1 in dopamine neurons, resilience
- cell type
- GRIN1 is not measured in dopamine neurons; looking elsewhere.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for GRIN1 in dopamine neurons.
case closed: nothing better to follow up.
receipt 0029: GRIN1 in dopamine neurons, braak
- cell type
- GRIN1 is not measured in dopamine neurons; looking elsewhere.
- cell type
- strongest in microglia: +0.30 (p 0.0058, n 84). proposing microglia.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GRIN1 in dopamine neurons.
case closed: every proposal failed a challenge.
Receipts
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