Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.55 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in brain excitatory neurons (367 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: disopyramide, indecainide, tetracaine hydrochloride +70 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 4 Parkinson's papers of 533 | 0.79 |
| pathways Reactome | 2 pathways; mostly other | 0.30 |
Knock down and overexpress SCN8A 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 SCN8A 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.
Earlier readings: 2026-10-26 0.57; 2026-10-25 0.57; 2026-10-24 0.57; 2026-10-23 0.57.
Sealed predictions
- SCN8A in dopamine neurons, braak+0.51 (p 5.4e-4) → +0.56 (p 1.0e-4)held
- SCN8A in dopamine neurons, braak+0.11 (p 0.773) → +0.11 (p 0.784)receipt 0584
- SCN8A in dopamine neurons, resilience-0.32 (p 0.314) → -0.11 (p 0.671)receipt 0126
Swarm cases
receipt 0584: SCN8A in dopamine neurons, braak
- power
- full sample +0.17 (p 0.504, n 18), 95% CI -0.32 to +0.59. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.20 (p 0.429, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.20 (p 0.418, n 18). could be the mix.
- skeptic
- leave-one-out range +0.07 to +0.27, sign flips 0; without severely affected donors +0.17 (p 0.504, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SCN8A in dopamine neurons.
case closed: nothing better to follow up.
receipt 0126: SCN8A in dopamine neurons, resilience
- power
- full sample -0.20 (p 0.303, n 55), 95% CI -0.44 to +0.07. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: -0.26 (p 0.178, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: -0.07 (p 0.705, n 55). could be the mix.
- skeptic
- leave-one-out range -0.30 to -0.13, sign flips 0; without severely affected donors -0.14 (p 0.495, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- nigra beats resilience for SCN8A in dopamine neurons: +0.55 (p 5.0e-8, n 84). proposing nigra.
case closed: every proposal failed a challenge.
Receipts
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