Clusterin in the Central Nervous System Historical Overview

Clusterin was originally described as a major glycoprotein synthesized in the male reproductive systems of the ram and rat.1,2 Since then it has been identified in a wide range of biological fluids and tissues in many species.1,3-9 Identification of rat clusterin messenger ribonucleic acid (mRNA) to TRPM-2 (testosterone repressed prostatic message 2),10-12 a transcript found to be prevalent in vivo in involuting tissues whether induced in experimental models or naturally during development of the embryo, raised the question of a possible involvement of clusterin in programmed cell death.13,14 Reports by several independent groups of researchers on the upregulation of the clusterin gene in brains of hamsters infected with the scrapie agent15 and of humans afflicted with Alzheimer's disease (AD),16 epilepsy,17 or gliomas,17 as well as in the degenerating human retina18 gave support to the apoptosis hypothesis and generated strong interest in the role of clusterin in the central nervous system (CNS). It soon became clear that clusterin overexpression occurred in all types of insults to the CNS, ranging from degenerative conditions like AD,16,19 Pick's disease15 and multiple sclerosis,20 to other neuropathies such as gliomas and epilepsy,17 to retroviral infection (e.g., human immunodeficiency virus and Rous sarcoma virus20,21) and experimental injury such as deafferentation,16,22-24 neurotoxic lesions,16,25-27 ischemia,28-30 and induced status epilepticus.31

A direct role for clusterin in programmed cell death in the rat CNS was subsequently disclosed in a study by Garden and coworkers32 using in situ hybridization. The authors examined the pattern of clusterin mRNA expression in the developing rat embryo and found it not to correlate with regions undergoing developmental cell death. Rather, they found increasing clusterin message to be associated with neuronal differentiation. The fact that nearly every neuron in the adult forebrain was positive for clusterin mRNA made it unlikely that clusterin correlated with programmed cell death in the majority of cells expressing it. Consistent with these data and supportive of a role for clusterin in the maturation of the nervous tissue are the observations made by O'Bryan et al33 during neuronal development in the mouse. In the latter study, virtually all neurons were shown to be clusterin-positive by immunohistochemistry. Staining was observed in the earliest neurons, and the intensity increased in an age-dependent manner.

Clusterin in Normal Brain Functions and During Neurodegeneration, edited by Caleb E. Finch. ©1999 R.G. Landes Company.

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