Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | genetic association 0.36 (overall 0.25) | 0.36 |
| cell type Human Protein Atlas | expressed broadly, no clear home in brain cells | 0.40 |
| chemistry Open Targets | compounds already reach it: sildenafil citrate, sildenafil, avanafil +10 | 1.00 |
| trials ClinicalTrials.gov | 2 Parkinson's trials, 1 stopped | 0.60 |
| literature PubMed | 2 Parkinson's papers of 339 | 0.85 |
| pathways Reactome | 3 pathways; mostly other | 0.30 |
Knock down and overexpress PDE5A in a dopamine neuron, astrocyte and microglia tri-culture; measure a transcriptome-wide state shift (bulk RNA-seq) 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
- a transcriptome-wide state shift (bulk RNA-seq)
- Functional readout
- dopamine neuron survival after α-synuclein fibril challenge
- Rule-out
- If neither arm moves a transcriptome-wide state shift (bulk RNA-seq) 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 PDE5A in a tri-culture of iPSC dopamine neurons, astrocytes and microglia; n = 3 differentiations; readouts: a transcriptome-wide state shift (bulk RNA-seq); 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
- PDE5A in dopamine neurons, braak+0.74 (p 0.023) → +0.18 (p 0.639)receipt 1722
Swarm cases
receipt 1722: PDE5A in dopamine neurons, braak
- power
- full sample +0.49 (p 0.038, n 18), 95% CI +0.03 to +0.78. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.49 (p 0.039, n 18). holds up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.61 (p 0.0067, n 18). not the mix.
- skeptic
- leave-one-out range +0.42 to +0.59, sign flips 0; without severely affected donors +0.49 (p 0.038, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for PDE5A in dopamine neurons.
case closed: nothing better to follow up.
Receipts
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