Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.00 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: givinostat, tacedinaline, panobinostat +10 | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 1 Parkinson's papers of 883 | 0.91 |
| pathways Reactome | 9 pathways; mostly growth signalling | 0.60 |
Knock down and overexpress HDAC8 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 HDAC8 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
- HDAC8 in microglia, braak-0.18 (p 0.646) → -0.08 (p 0.842)receipt 16664
- HDAC8 in dopamine neurons, braak-0.64 (p 0.063) → +0.29 (p 0.456)receipt 16665
Swarm cases
receipt 16665: HDAC8 in dopamine neurons, braak
- power
- full sample -0.07 (p 0.774, n 18), 95% CI -0.52 to +0.41. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.07 (p 0.787, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.12 (p 0.633, n 18). could be the mix.
- skeptic
- leave-one-out range -0.18 to +0.04, sign flips 3; without severely affected donors -0.07 (p 0.774, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HDAC8 in dopamine neurons.
case closed: nothing better to follow up.
receipt 16664: HDAC8 in microglia, braak
- power
- full sample -0.26 (p 0.289, n 18), 95% CI -0.65 to +0.23. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.31 (p 0.214, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: -0.20 (p 0.434, n 18). could be the mix.
- skeptic
- leave-one-out range -0.40 to -0.15, sign flips 0; without severely affected donors -0.26 (p 0.289, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for HDAC8 in microglia.
case closed: nothing better to follow up.
Receipts
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