Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.38 from other evidence | 0.00 |
| cell type Human Protein Atlas | enriched in the midbrain (508 nTPM), where the nigral dopamine neurons sit | 0.90 |
| chemistry Open Targets | compounds already reach it: vilazodone, desvenlafaxine fumarate, methamphetamine +64 | 1.00 |
| trials ClinicalTrials.gov | 8 Parkinson's trials, 2 stopped | 0.80 |
| literature PubMed | 18 Parkinson's papers of 1,547 | 0.61 |
| pathways Reactome | 2 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress SLC6A4 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 SLC6A4 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
- SLC6A4 in dopamine neurons, braak-0.08 (p 0.842) → -0.02 (p 0.964)receipt 0702
Swarm cases
receipt 0702: SLC6A4 in dopamine neurons, braak
- power
- full sample -0.07 (p 0.794, n 18), 95% CI -0.52 to +0.41. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.04 (p 0.861, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.07 (p 0.794, n 18). could be the mix.
- skeptic
- leave-one-out range -0.20 to +0.04, sign flips 2; without severely affected donors -0.07 (p 0.794, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SLC6A4 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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