Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.09 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including brain excitatory neurons; strongest in retinal amacrine cells | 0.75 |
| chemistry Open Targets | compounds already reach it: gabapentin, phloroglucinol, mibefradil +16 | 1.00 |
| trials ClinicalTrials.gov | 1 Parkinson's trial, 0 stopped | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 2 pathways; mostly other | 0.30 |
Knock down and overexpress CACNA1I in dopamine neurons; measure a transcriptome-wide state shift (bulk RNA-seq) 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
- a transcriptome-wide state shift (bulk RNA-seq)
- 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 a transcriptome-wide state shift (bulk RNA-seq) 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 CACNA1I in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); 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
- CACNA1I in dopamine neurons, braak-0.34 (p 0.373) → -0.37 (p 0.323)receipt 2814
Swarm cases
receipt 2814: CACNA1I in dopamine neurons, braak
- power
- full sample -0.36 (p 0.137, n 18), 95% CI -0.71 to +0.12. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.39 (p 0.105, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.61 (p 0.0077, n 18). not the mix.
- skeptic
- leave-one-out range -0.50 to -0.28, sign flips 0; without severely affected donors -0.36 (p 0.137, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for CACNA1I in dopamine neurons.
case closed: nothing better to follow up.
Receipts
loading the receipts