Bauer, C.; Duplan, E.; Saint-George-Hyslop, P.; Checler, F. Potentially Pathogenic SORL1 Mutations Observed in Autosomal-Dominant Cases of Alzheimer’s Disease Do Not Modulate APP Physiopathological Processing. Cells2023, 12, 2802.
Bauer, C.; Duplan, E.; Saint-George-Hyslop, P.; Checler, F. Potentially Pathogenic SORL1 Mutations Observed in Autosomal-Dominant Cases of Alzheimer’s Disease Do Not Modulate APP Physiopathological Processing. Cells 2023, 12, 2802.
Bauer, C.; Duplan, E.; Saint-George-Hyslop, P.; Checler, F. Potentially Pathogenic SORL1 Mutations Observed in Autosomal-Dominant Cases of Alzheimer’s Disease Do Not Modulate APP Physiopathological Processing. Cells2023, 12, 2802.
Bauer, C.; Duplan, E.; Saint-George-Hyslop, P.; Checler, F. Potentially Pathogenic SORL1 Mutations Observed in Autosomal-Dominant Cases of Alzheimer’s Disease Do Not Modulate APP Physiopathological Processing. Cells 2023, 12, 2802.
Abstract
SORL1 gene encodes LR11/SorLA, a protein that binds -amyloid precursor protein (bAPP) and drives its intracellular trafficking. SORL1 mutations occurring frequently in a subset of familial cases of Alzheimer’s disease (AD) have been documented but their pathogenic potential is not yet clear and questions remain concerning their putative influence on the physiopathological processing of bAPP. We have assessed the influence of three SORL1 mutations that were described as likely disease-causing and that were associated with either benign (SorLA924) or severe (SorLA141 and SorLA511) AD phenotypes. We examined the influence of wild-type and mutants SorLA in transiently transfected HEK293 cells expressing either wild-type or Swedish mutated bAPP on bAPP expression, secreted Ab and sAPPa levels, intracellular Ab40 and Ab42 peptides, APP-CTFs (C99 and C83) expressions, a-, b- and g-secretases expressions and activities as well as Ab and CTFs-degrading enzymes. These paradigms were studied in control conditions or after pharmacological proteasomal modulation. We also established stably transfected CHO cells expressing wild-type SorLA and established the colocalization of wild-type SorLA and bAPP. Overall, although we mostly confirmed previous data concerning the influence of wild-type SorLA on bAPP processing, we were unable to evidence significant alterations triggered by our set of SorLA mutants, whatever the cells or pharmacological conditions examined. Our study however does not rule out the possibility that other AD-linked SORL1 mutations could indeed affect bAPP processing and that pathogenic mutations examined in the present study could interfere with other cellular pathways/triggers in AD.
Keywords
SORL1, mutations, secretases, bAPP, Ab peptides, C-terminal fragments, neprilysin, proteasome, degradation, cellular localization, transient and stable expressions.
Subject
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
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