title: Protein quality control by Rer1p in the early secretory pathway: from mechanism to implication in Alzheimer's disease.
abstract: γ-Secretase-mediated production of amyloid β from the amyloid precursor protein is recognized as a central player in the neuropathogenesis of Alzheimer's disease (AD). One of the most peculiar features of this enzymatic activity is the fact that it targets transmembrane domains of mostly type I integral membrane proteins and thus manages to proteolyse peptide bonds within the hydrophobic lipid bilayers. In addition, γ-secretase does not exert its activity solely towards amyloid precursor protein, but to an increasing number of membrane proteins, including Notch, cadherins, syndecans, and so on. Because of the requirement of intramembrane proteolysis for a plethora of signaling pathways and cellular processes during embryonic development and organ physiology, this enzyme has drawn a lot of attention in the past 20 years. γ-Secretase is a multimeric transmembrane complex consisting of the catalytic presenilin, nicastrin, presenilin enhancer 2 (PEN2) and anterior-pharynx defective-1 (APH1) subunits. Proper assembly into functional complexes requires quality control mechanisms associated with the early biosynthetic compartments and allows mature complexes to transit to distal compartments where its activity is required. We previously identified Retrieval to ER protein 1 (Rer1p) as the first negative regulator of the stepwise assembly of γ-secretase during endoplasmic reticulum-to-Golgi transport. We review here the state of the art on how Rer1p regulates complex assembly, particularly γ-secretase, and evaluate the therapeutic potential of such regulatory processes in the context of AD.
authors: VIB Center for the Biology of Disease, Gasthuisberg, O&N4, POB 6023000, Leuven, Belgium ; Department of Human Genetics, KU Leuven, 3000, Leuven, Belgium.
authors: Nathalie
authors: N
authors: Jurisch-Yaksi
authors: VIB Center for the Biology of Disease, Gasthuisberg, O&N4, POB 6023000, Leuven, Belgium ; Department of Human Genetics, KU Leuven, 3000, Leuven, Belgium.
authors: Wim
authors: W
authors: Annaert