Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced in other brain neurons (125 nCPM) | 1.00 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 11 Parkinson's papers of 288 | 0.67 |
| pathways Reactome | 6 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress KIF5A 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 KIF5A 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
- KIF5A in dopamine neurons, braak+0.05 (p 0.755) → +0.12 (p 0.463)receipt 0070
- KIF5A in dopamine neurons, resilience+0.32 (p 0.264) → -0.37 (p 0.183)receipt 0071
Swarm cases
receipt 0071: KIF5A in dopamine neurons, resilience
- power
- full sample +0.01 (p 0.966, n 55), 95% CI -0.26 to +0.27. the interval is wide: not enough donors to tell.
- confounder
- adjusted for age, sex and PMI: +0.00 (p 1.000, n 55). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.12 (p 0.542); controlling for it: +0.04 (p 0.850, n 55). could be the mix.
- skeptic
- leave-one-out range -0.07 to +0.11, sign flips 22; without severely affected donors +0.08 (p 0.709, n 46). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "differs in resilient donors (Lewy pathology, no parkinsonism)" for KIF5A in dopamine neurons.
case closed: nothing better to follow up.
receipt 0070: KIF5A in dopamine neurons, braak
- power
- full sample +0.07 (p 0.537, n 84), 95% CI -0.15 to +0.28. the interval sits on zero: probably nothing there.
- confounder
- adjusted for age, sex and PMI: +0.05 (p 0.663, n 84). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis -0.72 (p 1.8e-14); controlling for it: -0.01 (p 0.943, n 84). could be the mix.
- skeptic
- leave-one-out range +0.04 to +0.10, sign flips 0; without severely affected donors -0.00 (p 0.985, n 75). fragile.
- cell type
- strongest in astrocytes: +0.30 (p 0.0059, n 84) vs +0.07 in dopamine neurons. proposing astrocytes.
- axis
- no measure beats "tracks Braak Lewy-body stage" for KIF5A in dopamine neurons.
follow-up registered; not confirmed in ventral tegmental area.
follow-up KIF5A · astrocytes · braak: ventral tegmental area +0.25 p 0.025 (needs p < 0.0045)
Receipts
loading the receipts