Protein family review
This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.
Authors:
1Centre for Research in Neurodegenerative Diseases, University of Toronto, Queen's Park Crescent West, Toronto M5S 3H2, Canada
2Department of Medicine, University of Toronto, Queen's Park Crescent West, Toronto M5S 3H2, Canada
3Department of Medical Biophysics, University of Toronto, Queen's Park Crescent West, Toronto M5S 3H2, Canada
Correspondence:
Anurag Tandon.
Email:
Read the full article
Subscribers to GenomeBiology may view the full version of this review article online at http://genomebiology.com/2002/3/11/reviews/3014
Published:
23 October 2002
The presenilins
Summary
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 'γ-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 β 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.
Frontiers
The identification of the additional γ-secretase components within the presenilin complexes is clearly an important task that lies ahead. The complexes purified to date are quite large, partly because of membrane impurities that remain associated following treatment with gentle detergents and partly because of interacting proteins that are not related to γ-secretase activity but are necessary for trafficking and maturation of the complex. The genetic cause of at least half of all cases of early onset familial Alzheimer's disease remain unexplained, and some of the unknown genes may have products that may modulate presenilin activity within γ-secretase complexes.
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© BioMedCentral Ltd. Protein family reviews appear as regular features in GenomeBiology. A complete list of protein family reviews is available online at http://genomebiology.com/proteinfamilyreviews/
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