The presenilins and Alzheimer's disease.
The presenilin 1 and presenilin 2 genes have been identified as pathogenic loci involved in the majority of early onset, autosomal dominant Alzheimer's disease. A series of (predominantly) missense mutations have been identified in the two genes which lead to disease. The presenilins are probably eight transmembrane domain proteins with both termini in the cytoplasmic compartment. They have a wide tissue distribution and are found in the endoplasmic reticulum and early Golgi. The mechanism of pathogenesis of the mutations is not clear although, both in patients and in in vitro systems, the effects of presenilin mutations are reminiscent of the effects of the pathogenic mutations in the amyloid precursor protein gene which lead to increases in the amount of amyloid-beta42(43) being produced from the metabolism of the amyloid protein precursor. Thus, the presenilin data provide independent support for the amyloid cascade hypothesis of Alzheimer's pathogenesis. Work on the Caenorhabditis elegans homologues of the presenilins, spe-4 and sel-12, suggests that the presenilins may have a more general and direct role in the processing and trafficking of membrane-bound proteins and that, in part, the pathogenic mutations may disrupt this role.
Hutton
M
M
Neurogenetics Laboratory, The Mayo Clinic Jacksonville, FL 32224, USA. hutton.michael@mayo.edu
Hardy
J
J
D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D009154:Mutation; D053764:Presenilin-1; D053766:Presenilin-2; D017433:Protein Structure, Secondary
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