Presenilin-1 and -2 (PS1 and PS2) are members of a (growing) family of genes which encode polytopic integral transmembrane proteins homologous to the Notch cell surface receptors of Drosophila and the sel-12 element of the C. elegans gene (see Selkoe, Curr Opin Neurobiol 2000;10:50-57); Czech et al., Prog Neurobiol 2000;60:63-384). The PSs were reviewed to subserve putative membrane functions linked to signal transduction, neuronal development and degeneration. PS1 and PS2 behave as membrane molecular complexes; they can be cleaved internally to generate stable N- and C-terminal PS fragments (NTF/CTF). Maturation of this PS complex suggested that additional membrane-integral or peripherally associated components might be associated with this PS1/PS2 membranal complex.

Yu et al. (492.8) described the discovery of nicastrin, a novel transmembrane glycoprotein that forms high molecular weight intramembrane complexes with PS1 and PS2. It was found that suppression of nicastrin expression in C. elegans induces a subset of Notch/GLP-1 phenotypes. Nicastrin was also shown to bind to the carboxy-terminal of β-amyloid precursor protein (βAPP) and thereby modulated the production of Aβ from β-amyloid precursor protein. It was also reported that missense mutations in a highly conserved hydrophilic domain of nicastrin increased the secretion of Aβ peptides. In conclusion, PS1 or PS2 and nicastrin are thought to form high molecular weight integral membrane protein complexes which (a) may represent key components of the intramembranous proteolysis of proteins implicated in AD neuropathology (such as Notch/GLP-1 and βAPP) and (b) may have a more general role as a “secretosome” in scavenging, processing or catabolizing intramembranal and/or membrane associated peripheral proteins. (See Yu et al., Nature 2000 407.)—Walter Lukiw
References: 492.8 Yu G, Holmes E, Yang DS, Chen F, Nishimura M, Tandon A, Fraser P, St George-Hyslop P. Nicastrin—An analysis of the formation and maturation of the presenilin complexes in Alzheimer's disease.

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