Brain clusterin protein isoforms and mitochondrial localization.

Sarah K Herring,Anindit Chhibber,Liqin Zhao,Punam Rawal,Hee-Jung Moon

doi:10.7554/elife.48255

Abstract

Clusterin (CLU), or apolipoprotein J (ApoJ), is the third most predominant genetic risk factor associated with late-onset Alzheimer's disease (LOAD). In this study, we use multiple rodent and human brain tissue and neural cell models to demonstrate that CLU is expressed as multiple isoforms that have distinct cellular or subcellular localizations in the brain. Of particular significance, we identify a non-glycosylated 45 kDa CLU isoform (mitoCLU) that is localized to the mitochondrial matrix and expressed in both rodent and human neurons and astrocytes. In addition, we show that rodent mitoCLU is translated from a non-canonical CUG (Leu) start site in Exon 3, a site that coincides with an AUG (Met) in human CLU. Last, we reveal that mitoCLU is present at the gene and protein level in the currently available CLU-/- mouse model. Collectively, these data provide foundational knowledge that is integral in elucidating the relationship between CLU and the development of LOAD.

Highlights

Late-onset Alzheimer’s disease (LOAD) is the most common form of Alzheimer’s disease (AD) representing more than 95% of all AD cases
Multiple CLU protein isoforms are robustly expressed in rodent brain tissue Previous studies have indicated the expression of CLU mRNA in multiple tissue types, with mRNA predominantly detected in the central nervous system (CNS) (Connor et al, 2001; de Silva et al, 1990a)
The data indicate the expression of four major CLU immunoreactive bands in a whole-brain lysate [CLU_49 kDa, CLU_45 kDa, CLU_39 kDa, and CLU_36 kDa (Figure 1A)], an expression pattern that was consistent throughout multiple brain regions [cortex, hippocampus, hypothalamus, and cerebellum; (Supplementary Figure A)]

Summary

Introduction

Late-onset Alzheimer’s disease (LOAD) is the most common form of Alzheimer’s disease (AD) representing more than 95% of all AD cases. Of the dozens of genetic risk factors that have been associated with increased risk for LOAD, two members of the apolipoprotein family reside in the top three: apolipoprotein E (ApoE) and apolipoprotein J (ApoJ), known as clusterin (CLU) (Alzforum Networking, 2019). While the risk conferred by ApoE has been extensively characterized, the identification of CLU as a genetic risk factor is relatively recent (Harold et al, 2009; Lambert et al, 2009). Despite this novelty, it is established that the CLU polymorphism rs11136000 confers an increased risk of developing LOAD that is independent of ApoE e4 status. As nearly 36% of the Caucasian population carries this CLU risk genotype (Bertram et al, 2007; Braskie et al, 2011), a thorough understanding of the physiological properties and roles of CLU in the brain is crucial for understanding the pathophysiological impact of CLU in LOAD

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