Genetics of clusterin isoform expression and Alzheimer's disease risk.

I-Fang Ling,Jiraganya Bhongsatiern,David W Fardo,James F Simpson,Steven Estus,Tsuneya Ikezu

doi:10.1371/journal.pone.0033923

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.

Highlights

Clusterin (CLU, APOJ) has been implicated in diseases ranging from cancer to Alzheimer’s disease (AD)
The primary role of clusterin in AD is unclear, CLU is implicated in AD by several lines of evidence, including (I) CLU mRNA and clusterin protein is increased in AD [5,6], (ii) clusterin is a component of plaques [4,5,7], (iii) clusterin modulates ADrelated pathways such as inflammation and apoptosis [1,8,9] and (iv) clusterin acts as an amyloid-beta (Aß) chaperone to alter Aß aggregation and/or clearance ([10,11], reviewed in [4,12,13,14])
The expression of only CLU1 was associated with rs11136000 while both CLU1 and CLU2 were increased with robust AD neuropathology

Summary

Introduction

Clusterin (CLU, APOJ) has been implicated in diseases ranging from cancer to Alzheimer’s disease (AD) (reviewed in [1,2,3,4]). How CLU SNPs modulate clusterin to alter AD risk is unknown. Two CLU isoforms, CLU1 and CLU2, have been reported that consist of nine exons and differ only in their first exons and associated proximal promoters; CLU1 is predicted to encode a nuclear protein and CLU2 a secreted protein (reviewed in [20]). Additional reported isoforms include a CLU isoform that lacks exon 5 and a CLU isoform that lacks exon two, which encodes the leader sequence, resulting in another nuclear clusterin [21,22].

Methods

Results

Conclusion