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 astrocytes; strongest in retinal amacrine cells | 0.75 |
| chemistry Open Targets | a small-molecule pocket | 0.60 |
| 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 | 16 pathways; mostly immune signalling | 0.90 |
Knock down and overexpress ADCY8 in astrocytes; measure IL-1β and TNF release and surface HLA-DR and α-synuclein uptake and degradation, and dopamine neuron survival in co-culture.
- Cell type
- astrocytes
- Direction
- Both arms: public data does not say which way helps.
- Molecular readout
- IL-1β and TNF release and surface HLA-DR
- Functional readout
- α-synuclein uptake and degradation, and dopamine neuron survival in co-culture
- Rule-out
- If neither arm moves IL-1β 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 ADCY8 in iPSC-derived midbrain astrocytes; n = 3 differentiations; readouts: IL-1β and TNF release and surface HLA-DR; α-synuclein uptake and degradation, and dopamine neuron survival in co-culture. Controls: non-targeting guide, empty vector. About 8 to 10 weeks, most of it differentiation.
Sealed predictions
- ADCY8 in astrocytes, braak+0.56 (p 0.116) → +0.75 (p 0.019)receipt 16059
- ADCY8 in dopamine neurons, braak-0.37 (p 0.324) → -0.01 (p 0.982)receipt 16060
Swarm cases
receipt 16060: ADCY8 in dopamine neurons, braak
- power
- full sample -0.17 (p 0.504, n 18), 95% CI -0.59 to +0.32. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.17 (p 0.504, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: -0.19 (p 0.439, n 18). could be the mix.
- skeptic
- leave-one-out range -0.26 to -0.06, sign flips 0; without severely affected donors -0.17 (p 0.504, n 18). fragile.
- cell type
- strongest in astrocytes: +0.64 (p 0.0044, n 18) vs -0.17 in dopamine neurons. proposing astrocytes.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ADCY8 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up ADCY8 · astrocytes · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) +0.07 p 0.790 (needs p < 1.4e-4)
receipt 16059: ADCY8 in astrocytes, braak
- power
- full sample +0.64 (p 0.0044, n 18), 95% CI +0.24 to +0.85. the interval excludes zero: something may be there, smaller than a half can see.
- confounder
- adjusted for sex: +0.64 (p 0.0040, n 18). holds up.
- composition
- astrocytes share of nuclei vs axis -0.21 (p 0.413); controlling for it: +0.64 (p 0.0040, n 18). not the mix.
- skeptic
- leave-one-out range +0.59 to +0.73, sign flips 0; without severely affected donors +0.64 (p 0.0044, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for ADCY8 in astrocytes.
case closed: nothing better to follow up.
Receipts
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