Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.31 (overall 0.20) | 0.31 |
| cell type Human Protein Atlas | cell type enhanced in brain inhibitory neurons (185 nCPM) | 1.00 |
| chemistry Open Targets | reachable by antibody | 0.45 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 0 stopped | 1.00 |
| literature PubMed | 48 Parkinson's papers of 4,077 | 0.49 |
| pathways Reactome | 6 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress NSF in dopamine neurons; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position 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.
- Molecular readout
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- 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 LRRK2 kinase activity (pT73-Rab10) 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 NSF in iPSC-derived midbrain dopamine neurons (FOXA2+, LMX1A+, TH+); n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; 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
- NSF in dopamine neurons, braak+0.14 (p 0.714) → +0.16 (p 0.672)receipt 2022
Swarm cases
receipt 2022: NSF in dopamine neurons, braak
- power
- full sample +0.08 (p 0.767, n 18), 95% CI -0.41 to +0.52. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.09 (p 0.709, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.11 (p 0.658, n 18). could be the mix.
- skeptic
- leave-one-out range -0.04 to +0.19, sign flips 3; without severely affected donors +0.08 (p 0.767, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for NSF in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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