Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.10 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in choroid plexus epithelial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: panobinostat, cudc-101, fimepinostat +9 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 3 Parkinson's papers of 557 | 0.82 |
| pathways Reactome | 5 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress HDAC9 in microglia; measure phospho-ERK and phospho-AKT response to GDNF and uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release).
- Cell type
- microglia
- Direction
- Both arms: public data does not say which way helps; existing compounds already reach the inhibition arm.
- Molecular readout
- phospho-ERK and phospho-AKT response to GDNF
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves phospho-ERK 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 HDAC9 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: phospho-ERK and phospho-AKT response to GDNF; uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release). Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- HDAC9 in microglia, braak-0.02 (p 0.962) → +0.17 (p 0.670)receipt 2768
- HDAC9 in dopamine neurons, braak+0.51 (p 0.161) → +0.16 (p 0.685)receipt 2769
Swarm cases
receipt 2769: HDAC9 in dopamine neurons, braak
- power
- full sample +0.33 (p 0.188, n 18), 95% CI -0.17 to +0.69. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.33 (p 0.188, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.33 (p 0.188, n 18). could be the mix.
- skeptic
- leave-one-out range +0.23 to +0.48, sign flips 0; without severely affected donors +0.33 (p 0.188, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HDAC9 in dopamine neurons.
case closed: nothing better to follow up.
receipt 2768: HDAC9 in microglia, braak
- power
- full sample +0.01 (p 0.969, n 18), 95% CI -0.46 to +0.47. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.02 (p 0.935, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.03 (p 0.908, n 18). could be the mix.
- skeptic
- leave-one-out range -0.13 to +0.08, sign flips 6; without severely affected donors +0.01 (p 0.969, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HDAC9 in microglia.
case closed: nothing better to follow up.
Receipts
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