Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | group enriched in other brain neurons (57 nCPM) | 1.00 |
| chemistry Open Targets | compounds already reach it: ixazomib citrate, bortezomib, ixazomib +4 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | no papers tie it to Parkinson's yet | 1.00 |
| pathways Reactome | 69 pathways; mostly vesicle traffic | 1.00 |
Knock down and overexpress PSMA6 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; existing compounds already reach the inhibition arm.
- 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 PSMA6 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
- PSMA6 in dopamine neurons, braak+0.45 (p 0.227) → +0.26 (p 0.502)receipt 9922
Swarm cases
receipt 9922: PSMA6 in dopamine neurons, braak
- power
- full sample +0.26 (p 0.294, n 18), 95% CI -0.23 to +0.65. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.27 (p 0.273, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.28 (p 0.265, n 18). could be the mix.
- skeptic
- leave-one-out range +0.17 to +0.39, sign flips 0; without severely affected donors +0.26 (p 0.294, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PSMA6 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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