Six readers
| reader | found | score |
|---|---|---|
| genetics Open Targets | no genetic evidence; overall 0.01 from other evidence | 0.00 |
| cell type Human Protein Atlas | cell type enhanced, including microglia; strongest in papillary tip epithelial 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 | 2 Parkinson's papers of 167 | 0.85 |
| pathways Reactome | 1 pathway; mostly lysosome and autophagy | 1.00 |
Knock down and overexpress SGPL1 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 SGPL1 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
- SGPL1 in microglia, braak-0.39 (p 0.300) → +0.43 (p 0.251)receipt 10540
- SGPL1 in dopamine neurons, braak+0.02 (p 0.965) → +0.37 (p 0.321)receipt 10541
Swarm cases
receipt 10541: SGPL1 in dopamine neurons, braak
- power
- full sample +0.21 (p 0.413, n 18), 95% CI -0.29 to +0.61. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.18 (p 0.482, n 18). does not hold up.
- composition
- dopamine neurons share of nuclei vs axis +0.05 (p 0.854); controlling for it: +0.08 (p 0.761, n 18). could be the mix.
- skeptic
- leave-one-out range +0.10 to +0.31, sign flips 0; without severely affected donors +0.21 (p 0.413, n 18). fragile.
- cell type
- strongest in OPCs: -0.70 (p 0.0011, n 18) vs +0.21 in dopamine neurons. proposing OPCs.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SGPL1 in dopamine neurons.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up SGPL1 · OPCs · braak: substantia nigra, an independent cohort (already registered)
receipt 10540: SGPL1 in microglia, braak
- power
- full sample +0.08 (p 0.767, n 18), 95% CI -0.41 to +0.52. the interval is wide: not enough donors to tell.
- confounder
- adjusted for sex: +0.11 (p 0.671, n 18). does not hold up.
- composition
- microglia share of nuclei vs axis -0.11 (p 0.652); controlling for it: +0.12 (p 0.646, n 18). could be the mix.
- skeptic
- leave-one-out range -0.05 to +0.20, sign flips 2; without severely affected donors +0.08 (p 0.767, n 18). fragile.
- cell type
- strongest in OPCs: -0.70 (p 0.0011, n 18) vs +0.08 in microglia. proposing OPCs.
- axis
- no measure beats "tracks Braak Lewy-body stage" for SGPL1 in microglia.
follow-up registered; not confirmed in substantia nigra, an independent cohort.
follow-up SGPL1 · OPCs · braak: substantia nigra, an independent cohort (Parkinson's or LBD vs controls) -0.20 p 0.477 (needs p < 2.1e-4)
Receipts
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