Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.28 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in brain inhibitory neurons (1299 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: basimglurant, azd2516, azd2066 +6 | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 5 Parkinson's papers of 167 | 0.76 |
| pathways Reactome | 3 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress GRM5 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 GRM5 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.
Sealed predictions
- GRM5 in dopamine neurons, braak+0.22 (p 0.569) → +0.53 (p 0.146)receipt 1445
Swarm cases
receipt 1445: GRM5 in dopamine neurons, braak
- power
- full sample +0.51 (p 0.030, n 18), 95% CI +0.06 to +0.79. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.51 (p 0.030, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.53 (p 0.025, n 18). not the mix.
- skeptic
- leave-one-out range +0.45 to +0.70, sign flips 0; without severely affected donors +0.51 (p 0.030, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GRM5 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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