Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.07 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including brain excitatory neurons; strongest in thyrotrophs | 0.75 |
| chemistry Open Targets | compounds already reach it: amifampridine phosphate, guanidine hydrochloride, nerispirdine +5 | 1.00 |
| trials ClinicalTrials.gov | 6 Parkinson's trials, 1 stopped | 0.87 |
| literature PubMed | 12 Parkinson's papers of 173 | 0.66 |
| pathways Reactome | 2 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress KCND3 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; existing compounds already reach the inhibition arm.
- 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 KCND3 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
- KCND3 in dopamine neurons, braak-0.01 (p 0.982) → -0.76 (p 0.017)receipt 3867
Swarm cases
receipt 3867: KCND3 in dopamine neurons, braak
- power
- full sample -0.27 (p 0.273, n 18), 95% CI -0.66 to +0.22. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.25 (p 0.310, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.38 (p 0.118, n 18). could be the mix.
- skeptic
- leave-one-out range -0.44 to -0.18, sign flips 0; without severely affected donors -0.27 (p 0.273, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KCND3 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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