The presenilins - PubMed (original) (raw)

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The presenilins

Anurag Tandon et al. Genome Biol. 2002.

Abstract

The presenilins are evolutionarily conserved transmembrane proteins that regulate cleavage of certain other proteins in their transmembrane domains. The clinical significance of this regulation is shown by the contribution of presenilin mutations to 20-50% of early-onset cases of inherited Alzheimer's disease. Although the precise molecular mechanism underlying presenilin function or dysfunction remains elusive, presenilins are thought to be part of a complex of proteins that has 'gamma-secretase cleavage' activity, which is clearly central in the pathogenesis of Alzheimer's disease. Mutations in presenilins increase the production of the longer isoforms of amyloid beta peptide, which are neurotoxic and prone to self-aggregation. Biochemical studies indicate that the presenilins do not act alone but operate within large heteromeric protein complexes, whose components and enzymatic core are the subject of much study and controversy; one essential component is nicastrin. The presenilin primary sequence is remarkably well conserved in eukaryotes, suggesting some functional conservation; indeed, defects caused by mutations in the nemotode presenilin homolog can be rescued by human presenilin.

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Figures

Figure 1

Figure 1

A molecular model of Presenilin-1. The protein is thought to have eight transmembrane domains. Residues associated with mutations found in familial Alzheimer's disease are colored as indicated in the key. 'Endoproteolysis' indicates the approximate site of the imprecise cleavage of the molecule.

Figure 2

Figure 2

The role of presenilins in the γ-secretase cleavage of Notch and βAPP. Notch is cleaved by tumor necrosis factor α converting enzyme (TACE), and its ligand binds to the part of Notch that remains attached to the membrane. βAPP is cleaved by either the γ-secretase pathway or the γ-secretase pathway to give a membrane-bound carboxy-terminal fragment (APP-CTF). Subsequent γ-secretase cleavage (in the transmembrane domain) of Notch or APP-CTF produces carboxy-terminal intracellular domains, NICD and AICD, respectively, which enter the nucleus and are thought to regulate gene expression. The γ-secretase cleavage of βAPP also produces the neurotoxic Aβ peptide, but only if βAPP has been first cleaved by γ-secretase (not γ-secretase). The γ-secretase complex includes, in addition to PS1, the presenilin-binding protein nicastrin; members of the Armadillo protein family, such as β-catenin, have also been detected in presenilin complexes, although their role is not understood. Aph-1 and Pen-2 may also participate in the γ-secretase complex.

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