title: Genetics of clusterin isoform expression and Alzheimer's disease risk.
abstract: The minor allele of rs11136000 within CLU is strongly associated with reduced Alzheimer's disease (AD) risk. The mechanism underlying this association is unclear. Here, we report that CLU1 and CLU2 are the two primary CLU isoforms in human brain; CLU1 and CLU2 share exons 2-9 but differ in exon 1 and proximal promoters. The expression of both CLU1 and CLU2 was increased in individuals with significant AD neuropathology. However, only CLU1 was associated with the rs11136000 genotype, with the minor "protective" rs11136000T allele being associated with increased CLU1 expression. Since CLU1 and CLU2 are predicted to encode intracellular and secreted proteins, respectively, we compared their expression; for both CLU1 and CLU2 transfected cells, clusterin is present in the secretory pathway, accumulates in the extracellular media, and is similar in size to clusterin in human brain. Overall, we interpret these results as indicating that the AD-protective minor rs11136000T allele is associated with increased CLU1 expression. Since CLU1 and CLU2 appear to produce similar proteins and are increased in AD, the AD-protection afforded by the rs11136000T allele may reflect increased soluble clusterin throughout life.
authors.affiliation: Department of Physiology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Ling
authors.forename: Jiraganya
authors.initials: J
authors.lastname: Bhongsatiern
authors.forename: James F
authors.initials: JF
authors.lastname: Simpson
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.forename: Steven
authors.initials: S
authors.lastname: Estus
mesh_terms: D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D001344:Autopsy; D001921:Brain / Q000378:metabolism / Q000502:physiology; D051152:Clusterin / Q000096:biosynthesis* / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000235:genetics; D005091:Exons; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006056:Golgi Apparatus / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D014407:Tumor Cells, Cultured
chemical_list: C495242:CLU protein, human; D051152:Clusterin; D020033:Protein Isoforms