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- W2980703752 abstract "SorLA is a neuronal sorting receptor implicated in sporadic and familial forms of Alzheimer's disease (AD). Receptor activity decreases the amyloidogenic cleavages of the Amyloid precursor protein, in agreement with findings of reduced sorLA expression in neurons from AD patients. Soluble receptor level in cerebrospinal fluid has therefore been suggested as a novel AD biomarker. However, the molecular determinants that regulate shedding of the sorLA ectodomain are poorly understood. Cell cultures, Western blot analysis, surface biotinylation, 35S-pulse-chase, deglycosylation, CRISPR-Cas gene knockout. Here, we show that sorLA exists as two distinct N-glycosylation variants at the cell surface, one with only high-mannose glycans and one with mainly complex-type N-glycans. Using MGAT1 deficient cells we discovered that only the sorLA variant with matured complex N-glycans is shed by a TACE-mediated shedding process. By further studying the sorting variants of sorLA and chemical inhibition of their retrograde transport, we provide evidence that the maturation step priming sorLA to become a TACE substrate strongly depends on its ability to undergo retrograde sorting after internalization. This may explain why the ratio between the two cellular glycoforms varies for sorLA defective in certain trafficking steps, and thus provides a mechanism why shedding is compromised by certain mutations in sorLA. These findings suggest regulation of TACE through trafficking-dependent glycosylation, and will be useful for better understanding the biology of naturally occurring sorLA mutants found in patients with AD." @default.
- W2980703752 created "2019-10-25" @default.
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- W2980703752 date "2019-07-01" @default.
- W2980703752 modified "2023-09-28" @default.
- W2980703752 title "P4-516: GLYCOSYLATION-SPECIFIC SHEDDING OF SORLA/SORL1 REVEALS A NOVEL REGULATORY MECHANISM FOR TACE CLEAVAGE" @default.
- W2980703752 doi "https://doi.org/10.1016/j.jalz.2019.08.062" @default.
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