biostudies-literatureFazeli ENovo Nordisk FoundationAarhus Universitet111136https://www.ebi.ac.uk/biostudies/studies/S-EPMC12860930biostudies-literatureUnknown302(2)Growing evidence suggests that defects in endosomal recycling are a causal mechanism for Alzheimer's disease (AD). Sortilin-like receptor 1 (SORL1) is an endosomal sorting receptor that acts together with the retromer complex to facilitate shuttling of cargo from endosomes back to the trans-Golgi network or to the cell surface. Accumulating data indicate that SORL1 dysfunction contributes to AD pathogenesis. SORL1 is trafficked from the endosome to the cell surface in a retromer-dependent process, where it undergoes enzymatic cleavage, resulting in shedding of the SORL1 ectodomain (also known as soluble SORL1). We capitalized on this physiological process to develop and validate a cell-based luminescent reporter assay incorporating enhanced Gaussia luciferase (eGLuc) to quantify soluble SOThe Journal of biological chemistryA luminescent reporter assay to quantify SORL1 ectodomain shedding and retromer-dependent endosome recycling activity.PMC12860930NNF20OC0064162Andersen OMHuber AKFazeli EJan AJensen AMGMerchant KKlein JfalseA luminescent reporter assay to quantify SORL1 ectodomain shedding and retromer-dependent endosome recycling activity.Growing evidence suggests that defects in endosomal recycling are a causal mechanism for Alzheimer's disease (AD). Sortilin-like receptor 1 (SORL1) is an endosomal sorting receptor that acts together with the retromer complex to facilitate shuttling of cargo from endosomes back to the trans-Golgi network or to the cell surface. Accumulating data indicate that SORL1 dysfunction contributes to AD pathogenesis. SORL1 is trafficked from the endosome to the cell surface in a retromer-dependent process, where it undergoes enzymatic cleavage, resulting in shedding of the SORL1 ectodomain (also known as soluble SORL1). We capitalized on this physiological process to develop and validate a cell-based luminescent reporter assay incorporating enhanced Gaussia luciferase (eGLuc) to quantify soluble SO2026-01-01T00:00:00Z2026 Jan2026-07-14T17:19:19.966Z2026-06-21T03:13:08.684ZS-EPMC128609304151920010.1016/j.jbc.2026.111136