γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors
Open Access
- 2 December 2020
- journal article
- research article
- Published by Frontiers Media SA in Frontiers in Aging Neuroscience
Abstract
Described as the “proteasome of the membrane” or the “scissors in the membrane,” γ-secretase has notoriously complicated biology, and even after decades of research, the full extent of its regulatory mechanism remains unclear. γ-Secretase is an intramembrane aspartyl protease complex composed of four obligatory subunits: Nicastrin (NCT), Presenilin (PS), Presenilin Enhancer-2 (Pen-2), and Anterior pharynx-defective-1 (Aph-1). γ-Secretase cleaves numerous type 1 transmembrane substrates, with no apparent homology, and plays major roles in broad biological pathways such as development, neurogenesis, and cancer. Notch and the amyloid precursor protein (APP) and are undoubtedly the best-studied γ-secretase substrates because of their role in cancer and Alzheimer’s disease (AD) and therefore became the focus of increasing studies as an attractive therapeutic target. The regulation of γ-secretase is intricate and involves the function of multiple cellular entities. Recently, γ-secretase modulatory proteins (GSMPs), which are non-essential subunits and yet modulate γ-secretase activity and specificity, have emerged as an important component in guiding γ-secretase. GSMPs are responsive to cellular and environmental changes and therefore, provide another layer of regulation of γ-secretase. This type of enzymatic regulation allows for a rapid and fine-tuning of γ-secretase activity when appropriate signals appear enabling a temporal level of regulation. In this review article, we discuss the latest developments on GSMPs and implications on the development of effective therapeutics for γ-secretase-associated diseases such as AD and cancer.Keywords
This publication has 110 references indexed in Scilit:
- Activation and intrinsic γ-secretase activity of presenilin 1Proceedings of the National Academy of Sciences of the United States of America, 2010
- Gamma-secretase activating protein is a therapeutic target for Alzheimer’s diseaseNature, 2010
- Characterization of an Atypical γ-Secretase Complex from Hematopoietic OriginBiochemistry, 2010
- Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapyNature Reviews Neuroscience, 2009
- Pen2 and Presenilin-1 Modulate the Dynamic Equilibrium of Presenilin-1 and Presenilin-2 γ-Secretase ComplexesJournal of Biological Chemistry, 2009
- Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOEAmerican Journal of Human Genetics, 2008
- Direct and Potent Regulation of γ-Secretase by Its Lipid MicroenvironmentOnline Journal of Public Health Informatics, 2008
- Loss‐of‐function presenilin mutations in Alzheimer diseaseEMBO Reports, 2007
- When loss is gain: reduced presenilin proteolytic function leads to increased Aβ42/Aβ40EMBO Reports, 2007
- Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's diseaseNature, 1991