A Role for Clusterin in Exfoliation Syndrome and Exfoliation Glaucoma?

Abstract

The multifunctional protein clusterin (CLU) is a secreted glycoprotein ubiquitously expressed throughout the body, including in the eye. Its primary function is to act as an extracellular molecular chaperone, preventing the precipitation and aggregation of misfolded extracellular proteins. Clusterin is commonly identified at fluid-tissue interfaces, and has been identified in most body fluids. It is a component of exfoliation material, and CLU mRNA is reduced in eyes with exfoliation syndrome compared with controls. SNPs located in the CLU genomic region have been associated with Alzheimer disease (AD) at the genome-wide level and several CLU SNPs located in an apparent regulatory region have been nominally associated with XFS/XFG in Caucasians with European ancestry and in south Indians. Interestingly, clusterin associates with altered elastic fibers in human photoaged skin and prevents UV-induced elastin aggregation in vitro. In light of the known geographic risk factors for XFS/XFG, which could include UV light, investigations of CLU-geographic interactions could be of interest. Future studies investigating rare CLU variation and other complex interactions including gene-gene interactions in XFS/XFG cases and controls may also be fruitful. Although CLU has been considered as a therapeutic target in AD, cancer and dry eye, a role for clusterin in XFS/XFG needs to be better defined before therapeutic approaches involving CLU can be entertained.

Figure 1.

Biological and pathological processes involving clusterin.

Figure 2.. Features of the Clusterin gene (CLU) genomic region.

Clusterin gene (CLU) genomic region. The genomic location of the CLU exons (larger blue rectangles) and introns (blue lines) as depicted in the UCSC genome browser (http://ucsc.genome.edu) on chromosome 8 are shown. Beneath the exon/intron are the locations of the SNPs associated with Alzheimer disease (AD) (green type) and XFS/XFG (black type). rs2279590 is associated with both AD and XFS/XFG. The layered H3K27Ac histone marks (frequently found in regulatory regions) for 8 cell types studied by ENCODE are shown beneath the SNPs. rs3087554 and rs2279590 fall in a H3K27Ac peak in HUVEC cells (human umbilical vein). Rs3087554 and rs2279590 are also in the vicinity of a CLU miRNA binding site (miR-370) indicated in green below the H3K27Ac peaks.