γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors

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.

Genomics and Functional Genomics of Alzheimer's Disease

“…The catalytic activity of γ-secretase is determined by PSEN, which exists in two isoforms (PSEN1 and PSEN2). APH1 stabilizes the complex and has two isoforms (APH1A and APH1B), PEN2 is essential for γ-secretase maturation, and NCT plays a role in substrate binding [19][20][21][22].…”

Potential for Ketotherapies as Amyloid-Regulating Treatment in Individuals at Risk for Alzheimer’s Disease

“…Approximately 9–23% of humans express at least one APOE ε4 allele ( Jia et al, 2020 ), a prevalence that varies by race and ethnicity, which increases AD risk with even higher risk in APOE ε4 homozygotes ( Serrano-Pozo et al, 2011 ). Human APOE ε4 carriers consistently demonstrate higher Aβ burden and more rapid accumulation than non-carriers ( Tiraboschi et al, 2004 ; Drzezga et al, 2009 ; Caselli et al, 2010 ; Rowe et al, 2010 ; Baek et al, 2020 ), likely due to various effects including increased transcription of APP, potentially altered γ-secretase activity, interrupted Aβ degradation, and poor transport of Aβ across the blood brain barrier ( Huang et al, 2017 , 2019 ; Wong et al, 2020 ). We discuss the link between impaired brain bioenergetics and Aβ later, but individuals with ApoE ε4 exhibit brain hypometabolism as early as young adulthood ( Reiman et al, 2001 , 2004 ; Mosconi et al, 2008a ; Murray et al, 2014 ), which implicates impaired bioenergetics as a factor that mediates the influence of ApoE on Aβ.…”

Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

“…It remains unclear, whether this “proteasome-like activity” is nonselective and inactivates all substrates equally, or if some substrates are cleaved by specific protease complexes. Recent evidences seem to indicate at least some substrate specificity and that not only the exact protein composition of the secretase complex, but also the cellular context, subcellular localization, and the presence of nonessential cofactors ( 106 ) can be key determinants for this control. For instance, protease heterogeneity has been shown to be related to the exact protein composition of the protease and alternative splicing of Aph1 leads to further complexity ( 107 , 108 ).…”