Year: 2008
Type: article
Abstract: Mutations in PSEN1 and PSEN2 genes account for the majority of cases of early-onset familial Alzheimer disease (FAD). PSEN genes are ubiquitously expressed, and encode polytopic membrane proteins termed presenilins (PS), which function as the catalytic subunits of unusual transmembrane aspartyl proteases, termed γ-secretase. A wide spectrum of type I membrane protein substrates including amyloid precursor protein (APP) and Notch are processed by γ-secretase within their transmembrane domains. Since the genetic linkage between PSEN genes with FAD was identified a decade ago, significant insights regarding the physiological and pathological functions of PS have emerged from cell culture and animal model studies. γ-secretase cleavage of APP releases β-amyloid peptides. Familial Alzheimer's disease-associated presenilin variants exert their pathogenic function by altering the levels of Aβ40 and Aβ42 peptides generated by γ-secretase processing of APP. In addition, γ-secretase cleavage releases the intracellular domains of APP, Notch, and many other substrates, some of which engage in transcriptional signaling during development and in the adult. Finally, PS regulate endoplasmic reticulum calcium stores independent of γ-secretase activity, a function that is nevertheless impaired by pathogenic PSEN mutations. This talk will review the versatile functions of PS, and discuss recent developments in the cell biology of PS.
Source: Alzheimer s & Dementia
Author: Gopal Thinakaran
Institution: University of Chicago
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1985548282