Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.33 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enriched in other brain neurons (8 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: lisdexamfetamine dimesylate, nomifensine, bupropion +38 | 1.00 |
| trials ClinicalTrials.gov | 86 Parkinson's trials, 7 stopped | 0.89 |
| literature PubMed | 109 Parkinson's papers of 727 | 0.38 |
| pathways Reactome | 4 pathways; mostly dopamine synapse | 1.00 |
Knock down and overexpress SLC6A3 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 SLC6A3 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
- SLC6A3 in dopamine neurons, braak-0.35 (p 0.361) → -0.41 (p 0.273)receipt 0999
In the sealed studies
Swarm cases
receipt 0999: SLC6A3 in dopamine neurons, braak
- power
- full sample -0.17 (p 0.498, n 18), 95% CI -0.59 to +0.32. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.20 (p 0.424, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.14 (p 0.585, n 18). could be the mix.
- skeptic
- leave-one-out range -0.35 to -0.06, sign flips 0; without severely affected donors -0.17 (p 0.498, n 18). fragile.
- cell type
- strongest in astrocytes: -0.68 (p 0.0020, n 18) vs -0.17 in dopamine neurons. proposing astrocytes.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SLC6A3 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up SLC6A3 · astrocytes · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) -0.70 p 0.013 (needs p < 0.0013)
Receipts
loading the receipts