Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.08 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: alvespimycin, onalespib, luminespib +7 | 0.90 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 5 Parkinson's papers of 490 | 0.76 |
| pathways Reactome | 22 pathways; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress HSP90AB1 in a dopamine neuron, astrocyte and microglia tri-culture; measure glucocerebrosidase (GCase) activity and LC3-II and p62 flux 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
- glucocerebrosidase (GCase) activity and LC3-II and p62 flux
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves glucocerebrosidase (GCase) activity 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 HSP90AB1 in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: glucocerebrosidase (GCase) activity and LC3-II and p62 flux; 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
- HSP90AB1 in dopamine neurons, braak+0.32 (p 0.400) → +0.12 (p 0.767)receipt 3161
Swarm cases
receipt 3161: HSP90AB1 in dopamine neurons, braak
- power
- full sample +0.18 (p 0.476, n 18), 95% CI -0.31 to +0.60. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.23 (p 0.355, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.32 (p 0.191, n 18). could be the mix.
- skeptic
- leave-one-out range +0.08 to +0.29, sign flips 0; without severely affected donors +0.18 (p 0.476, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HSP90AB1 in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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