Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2.
Presenilin (PS)-1 is an intramembrane protease serving as the catalytic component of γ-secretase. Mutations in the PS1 gene are the most common cause of familial Alzheimer's disease (FAD). The low-density lipoprotein (LDL)-receptor family member apoER2 is a γ-secretase substrate that has been associated with AD in several ways, including acting as a receptor for apolipoprotein E (ApoE). ApoER2 is processed by γ-secretase into a C-terminal fragment (γ-CTF) that appears to regulate gene expression. FAD PS1 mutations were tested for effects on apoER2. PS1 mutation R278I showed impaired γ-secretase activity for apoER2 in the basal state or after exposure to Reelin. PS1 M146V mutation permitted accumulation of apoER2 CTFs after Reelin treatment, whereas no difference was seen between wild-type (WT) and M146V in the basal state. PS1 L282V mutation, combined with the γ-secretase inhibitor N-(N-[3,5-Difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester, greatly reduced the cell-surface levels of apoER2 without affecting total apoER2 levels, suggesting a defect in receptor trafficking. These findings indicate that impaired processing or localization of apoER2 may contribute to the pathogenic effects of FAD mutations in PS1.
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Wei
W
Wang
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Andrea M
AM
Moerman-Herzog
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Arthur
A
Slaton
Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Department of Neurobiology & Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Geriatrics Research, Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. Electronic address: bargerstevenw@uams.edu.
Steven W
SW
Barger
D000544:Alzheimer Disease / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000502:physiology; D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal; D002478:Cells, Cultured; D016326:Extracellular Matrix Proteins; D015870:Gene Expression; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins; D053764:Presenilin-1 / Q000235:genetics* / Q000502:physiology*; D000091042:Reelin Protein; D012697:Serine Endopeptidases
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D000091042:Reelin Protein; C098773:low density lipoprotein receptor-related protein 8; C580804:presenilin 1, mouse; D053829:Amyloid Precursor Protein Secretases; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases
Alzheimer's disease; ApoER2; Lipoprotein receptor; Presenilin; Protein processing; Protein trafficking; γ-Secretase