Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.37 (overall 0.23) | 0.37 |
| cell type Human Protein Atlas | cell type enhanced, including brain excitatory neurons; strongest in thyrotrophs | 0.75 |
| chemistry Open Targets | hard to drug | 0.27 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 6 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress RIMS1 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.
- 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 RIMS1 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
- RIMS1 in dopamine neurons, braak+0.06 (p 0.873) → +0.32 (p 0.399)receipt 1884
Swarm cases
receipt 1884: RIMS1 in dopamine neurons, braak
- power
- full sample +0.21 (p 0.393, n 18), 95% CI -0.28 to +0.62. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.23 (p 0.369, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.18 (p 0.476, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.34, sign flips 0; without severely affected donors +0.21 (p 0.393, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for RIMS1 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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