title: The presenilins.
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.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, University of Toronto, Queen's Park Crescent West, Toronto M5S 3H2, Canada. a.tandon@utoronto.ca
authors.forename: Anurag
authors.initials: A
authors.lastname: Tandon
authors.forename: Paul
authors.initials: P
authors.lastname: Fraser
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019143:Evolution, Molecular; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics / Q000502:physiology; D053764:Presenilin-1; D053766:Presenilin-2
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human