Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: ixazomib, bortezomib d-mannitol, oprozomib +4 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 36 | 0.91 |
| pathways Reactome | 69 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress PSMB3 in a dopamine neuron, astrocyte and microglia tri-culture; measure LRRK2 kinase activity (pT73-Rab10) and lysosome position and dopamine neuron survival after α-synuclein fibril challenge.
- Cell type
- a dopamine neuron, astrocyte and microglia tri-culture
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- LRRK2 kinase activity (pT73-Rab10) and lysosome position
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- 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 PSMB3 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: LRRK2 kinase activity (pT73-Rab10) and lysosome position; dopamine neuron survival after α-synuclein fibril challenge. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- PSMB3 in dopamine neurons, braak+0.08 (p 0.840) → -0.11 (p 0.787)receipt 9437
Swarm cases
receipt 9437: PSMB3 in dopamine neurons, braak
- power
- full sample +0.05 (p 0.840, n 18), 95% CI -0.43 to +0.51. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.14 (p 0.585, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.19 (p 0.450, n 18). could be the mix.
- skeptic
- leave-one-out range -0.07 to +0.17, sign flips 5; without severely affected donors +0.05 (p 0.840, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PSMB3 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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