Presenilins and γ-Secretase in Membrane Proteostasis

Abstract

The presenilin (PS) proteins exert a crucial role in the pathogenesis of Alzheimer disease (AD) by mediating the intramembranous cleavage of amyloid precursor protein (APP) and the generation of amyloid β-protein (Aβ). The two homologous proteins PS1 and PS2 represent the catalytic subunits of distinct γ-secretase complexes that mediate a variety of cellular processes, including membrane protein metabolism, signal transduction, and cell differentiation. While the intramembrane cleavage of select proteins by γ-secretase is critical in the regulation of intracellular signaling pathways, the plethora of identified protein substrates could also indicate an important role of these enzyme complexes in membrane protein homeostasis. In line with this notion, PS proteins and/or γ-secretase has also been implicated in autophagy, a fundamental process for the maintenance of cellular functions and homeostasis. Dysfunction in the clearance of proteins in the lysosome and during autophagy has been shown to contribute to neurodegeneration. This review summarizes the recent knowledge about the role of PS proteins and γ-secretase in membrane protein metabolism and trafficking, and the functional relation to lysosomal activity and autophagy.

Keywords: Alzheimer disease; autophagy; intramembrane proteolysis; membrane trafficking; presenilin; proteostasis; γ-secretase.

Figure 1

A schematic of the γ-secretase complex. Presenilins represent the catalytic components of γ-secretase complexes that contain three additional proteins presenilin-enhancer-2 (PEN2), nicastrin, and anterior-pharynx defective-1 (APH1). The aspartyl residues in transmembrane domains 6 and 7 required for catalytic activity are indicated by orange circles.

Figure 2

Impaired autophagy and lysosomal degradation in PS-deficient cells. (A) In wild-type cells, autophagy includes nucleation (1) and elongation of phagophores (2), autophagosome formation by phagophore maturation (3), autolysosome formation by the fusion of autophagosomes and lysosomes (4), and final degradation of the contents (5). (B) In PS-deficient cells, enlarged autophagic vacuoles accumulate and contain undigested engulfed material. The accumulation of autophagic vacuoles could result from the disturbed fusion of autophagosomes with lysosomes, probably caused by impaired lysosomal acidification (illustrated in a pale red color). Aberrant acidification could also affect calcium homeostasis in endolysosomal vesicles that could contribute to impaired vesicle fusion. PS deficiency can also impair amino acid sensing by mTORC1 on lysosomes and decrease activation and nuclear translocation of transcription factor EB (TFEB), thereby decreasing expression of proteins mediating biogenesis of lysosomal and autophagic vesicles. Decreased translocation of glycogen synthase kinase 3β (GSK3β) from the cytosol to the nucleus could also decrease the activation of TFEB. Increased acid sphingomyelinase (ASM) in PS-deficient cells can induce the accumulation of autophagic vacuoles. Decreased endocytosis in PS-deficient cells could also affect membrane protein and lipid homeostasis. Presenilin can be localized in the endoplasmic reticulum (ER), plasma membrane, endosomes (E), and lysosomes (LY). N, nucleus; TGN, trans-Golgi network.