Role of presenilin in gamma-secretase cleavage of amyloid precursor protein.
Cerebral accumulation of the amyloid beta-protein (Abeta) is an early and invariant event in the pathogenesis of Alzheimer's disease (AD). Mutations in the presenilin (PS) 1 and 2 genes that increase production of the highly amyloidogenic Abeta(42) are the most common cause of familial AD. Deletion of PS1 in mice reduces Abeta generation, indicating that PS1 mediates the last step in the generation of Abeta from beta-amyloid precursor protein (APP) by the unidentified gamma-secretase. Mutating either of two conserved transmembrane aspartates in PS1 significantly reduced Abeta production and increased the APP C-terminal fragments that are gamma-secretase substrates. These results indicate that PS1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase. Furthermore, studies on the gamma-secretase-like proteolytic processing of Notch and Ire1 suggest a common mechanism for the involvement of PS1 in intramembrane proteolysis of membrane proteins.
Xia
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Department of Neurology, Harvard Medical School, School and Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. xia@cnd.bwh.harvard.edu
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism*; D004722:Endoribonucleases; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D053764:Presenilin-1; D053766:Presenilin-2; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051880:Receptors, Notch
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D051880:Receptors, Notch; C403982:ERN2 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human