Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.30 from other evidence | 0.00 |
| cell type Human Protein Atlas | enriched in the midbrain (82 nTPM), where the nigral dopamine neurons sit | 0.90 |
| chemistry Open Targets | compounds already reach it: remimazolam, alprazolam, meprobamate +68 | 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 | in no curated pathway | 0.00 |
Knock down and overexpress GABRE 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 GABRE 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
- GABRE in dopamine neurons, braak-0.28 (p 0.472) → +0.33 (p 0.385)receipt 1293
Swarm cases
receipt 1293: GABRE in dopamine neurons, braak
- power
- full sample +0.05 (p 0.840, n 18), 95% CI -0.43 to +0.51. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.06 (p 0.827, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.09 (p 0.728, n 18). could be the mix.
- skeptic
- leave-one-out range -0.06 to +0.19, sign flips 4; without severely affected donors +0.05 (p 0.840, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for GABRE in dopamine neurons.
case closed: nothing better to follow up.
Receipts
loading the receipts