Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.03 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in vascular endothelial cells | 0.75 |
| chemistry Open Targets | compounds already reach it: technetium tc 99m succimer | 1.00 |
| trials ClinicalTrials.gov | no Parkinson's trials on record: an open field | 1.00 |
| literature PubMed | 16 Parkinson's papers of 813 | 0.63 |
| pathways Reactome | 4 pathways; mostly protein handling | 0.90 |
Knock down and overexpress A2M in microglia; measure proteasome activity and the load of ubiquitinated protein 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.
- Molecular readout
- proteasome activity and the load of ubiquitinated protein
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves proteasome 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 A2M in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: proteasome activity and the load of ubiquitinated protein; 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
- A2M in dopamine neurons, braak+0.72 (p 0.029) → +0.21 (p 0.581)receipt 6367
- A2M in microglia, braak+0.36 (p 0.348) → -0.01 (p 0.982)receipt 6366
Swarm cases
receipt 6367: A2M in dopamine neurons, braak
- power
- full sample +0.44 (p 0.069, n 18), 95% CI -0.04 to +0.75. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.43 (p 0.077, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.35 (p 0.159, n 18). could be the mix.
- skeptic
- leave-one-out range +0.36 to +0.54, sign flips 0; without severely affected donors +0.44 (p 0.069, n 18). robust.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for A2M in dopamine neurons.
case closed: nothing better to follow up.
receipt 6366: A2M in microglia, braak
- power
- full sample +0.15 (p 0.561, n 18), 95% CI -0.34 to +0.57. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.28 (p 0.269, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.28 (p 0.269, n 18). could be the mix.
- skeptic
- leave-one-out range +0.04 to +0.26, sign flips 0; without severely affected donors +0.15 (p 0.561, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for A2M in microglia.
case closed: nothing better to follow up.
Receipts
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