Detailed analysis of modulating effects of Clusterin in insulin and IGF-1 signal transduction
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Abstract
Despite intense research, only little is known concerning the interaction of Clusterin with signalling receptors or underlying mechanisms. In this work, the class of receptor tyrosine kinases are screened for potential interaction partners of Clusterin. This initial experiment revealed insulin receptor as a positive candidate for Clusterin-mediated signal transduction. The insulin receptor and its close relative, the IGF-1 receptor, are known to play crucial roles in the development of Alzheimer’s disease. Thus, the role of Clusterin in neuronal protection was assessed via the neuroblastoma cell line N2A. Subsequent analyses addressed modulating effects of Clusterin on Akt phosphorylation and its impact on the cellular viability in the presence of insulin/IGF-1. While the results for insulin were distorted by high levels of glucose in the culturing media, co-stimulation of Clusterin with IGF-1 revealed its enhancing effects on IGF-1 stimulation. By using biochemical methods and examining structural mutants of Clusterin, the interaction of IGF-1 with Clusterin was further elucidated. These methods demonstrated a distinct binding between both molecules and highlighted the necessity of structural domains of Clusterin. In conclusion, this thesis sheds light on the ability of Clusterin to modulate signal transduction pathways and evaluates its physiological role in Alzheimer’s disease.