Alpha-crystallin, a major component of the vertebrate lens, is composed of two subunits, the A Chain and the B Chain. These two proteins share many amino acid sequences, but show different patterns of tissue expression. While the A chain appears to be lens-specific, recent studies have demonstrated B chain in a variety of tissues, including cardiac and skeletal muscle, brain, kidney, peripheral nerve, and lung. Indeed, mRNA and protein levels in cardiac muscle approach those in lens. In the CNS, the B chain is found in glial cells, both astrocytes and oligodendrocytes. Although levels in normal CNS are low, B chain expression is increased in pathological circumstances, particularly those involving hypoxia and breakdown of the blood brain barrier. The most striking and bizarre expression of the B chain occurs in the brains of children with Alexander's disease, a degenerative disorder that typically affects young children and leads to death in a few years. In Alexander's disease, astrocytes throughout the CNS accumulate massive quantities of B chain, deposited on bundles of intermediate filaments. These accumulations have been called Rosenthal fibers, but until recently, nothing was known of their composition or origin. The structural properties, mRNA sequence, and genomic structures of both A and B chain have been studied extensively by investigators interested in lens proteins. Finding the B chain in other tissues opens up a large range of explorations into the biological features and regulation of this protein that have been difficult to approach in the lens. We propose to study several aspects of B chain expression outside the lens. Specifically, the following questions will be asked: 1. What is the subcellular localization of the B chain? It is an intermediate filament-associated protein? Is it a membrane-associated protein? 2. Is the 8 chain a """"""""stress"""""""" protein, regulated by pathological stimuli, and if so, what kinds of stimuli? 3. How might Rosenthal fibers be formed in astrocytes? These studies should shed new light on the properties of the alpha-crystallin B chain and illuminate how both lens epithelial cells and non-lens cells use this protein.
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