Charakterisierung der molekularen Faktoren bei der durch alpha-Crystallin induzierten zellulären Protektion gegen Apoptose

alpha-Crystallin is composed of two closely related subunits, alpha- and beta-Crystallin. There are three molecular species of crystallins, alpha-, beta- and gamma-Crystallin, predominant structural proteins in the mammalian eye lens. However, both crystallin subunits are also expressed in other tissues alpha-Crystallins can prevent apoptosis induced by factors like staurosporine, hydrogen peroxide or ultraviolet irradiation. For alpha-Crystallin the phosphorylation state seems to be important for the ability to protect cells against apoptosis. Under stress conditions, phosphorylation of alpha-Crystallin occurs on specific serine residues. alpha-Crystallins are also implicated in neurodegenerative diseases, like Alzheimers disease, Alexanders disesase and amyotrophic lateral sclerosis. Alpha-Crystallin is up-regulated in Alzheimers disease and occurs in amyloid plaques. These diseases are characterised by conformational changes in proteins resulting in misfolding and aggregation. The alpha-Crystallin expression is upregulated in response to cellular stress. It is suggested that alpha-Crystallins, as molecular chaperons, provide a defence mechanism against protein aggregation. We showed that overexpression of alpha-Crystallins can protect astrocytes from C2-ceramide and staurosporine-induced cell death and that alpha-Crystallin can interact with the protease-activated receptor-2 in the protection pathway. The molecular mechanism of the alpha-Crystallin-mediated cytoprotection in astrocytes and the role of PAR-2 during this process are still unkown. Thus, the aim of the project is to identify and characterise the molecular determinants and interacting proteins responsible for the protection against apoptosis to get a better understanding of the function of alpha-Crystallins in astrocytes.