Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.02 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in proximal tubule 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 | 4 Parkinson's papers of 461 | 0.79 |
| pathways Reactome | 3 pathways; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress SESN2 in microglia; measure glucocerebrosidase (GCase) activity and LC3-II and p62 flux 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
- glucocerebrosidase (GCase) activity and LC3-II and p62 flux
- Functional readout
- uptake and clearance of α-synuclein fibrils and NLRP3 inflammasome activation (IL-1β release)
- Rule-out
- If neither arm moves glucocerebrosidase (GCase) 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 SESN2 in iPSC-derived microglia (iMGL); n = 3 differentiations; readouts: glucocerebrosidase (GCase) activity and LC3-II and p62 flux; 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
- SESN2 in dopamine neurons, braak-0.21 (p 0.586) → -0.05 (p 0.893)receipt 8276
- SESN2 in microglia, braak+0.18 (p 0.638) → +0.28 (p 0.459)receipt 8275
Swarm cases
receipt 8276: SESN2 in dopamine neurons, braak
- power
- full sample -0.29 (p 0.239, n 18), 95% CI -0.67 to +0.20. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: -0.28 (p 0.265, 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 0.185, n 18). could be the mix.
- skeptic
- leave-one-out range -0.49 to -0.23, sign flips 0; without severely affected donors -0.29 (p 0.239, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SESN2 in dopamine neurons.
case closed: nothing better to follow up.
receipt 8275: SESN2 in microglia, braak
- power
- full sample +0.22 (p 0.374, n 18), 95% CI -0.27 to +0.62. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.13 (p 0.609, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.09 (p 0.728, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.36, sign flips 0; without severely affected donors +0.22 (p 0.374, n 18). fragile.
- cell type
- no other cell group does better.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SESN2 in microglia.
case closed: nothing better to follow up.
Receipts
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