Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.19 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including other brain neurons; strongest in epicardial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: ezlopitant, rolapitant, dnk333 +16 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 1 Parkinson's papers of 186 | 0.91 |
| pathways Reactome | 4 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress TACR1 in dopamine neurons; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- 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 LRRK2 kinase activity (pT73-Rab10) 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 TACR1 in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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
- TACR1 in dopamine neurons, braak-0.06 (p 0.888) → +0.09 (p 0.815)receipt 2050
Swarm cases
receipt 2050: TACR1 in dopamine neurons, braak
- power
- full sample +0.23 (p 0.351, n 18), 95% CI -0.26 to +0.63. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.20 (p 0.418, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.19 (p 0.450, n 18). could be the mix.
- skeptic
- leave-one-out range +0.14 to +0.39, sign flips 0; without severely affected donors +0.23 (p 0.351, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for TACR1 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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