Defective Signal Transduction and Oxidative Stress in Ataxia-Telangiectasia

Abstract

Ataxia-telangiectasia (A-T) is a debilitating disease caused by the functional loss of the ataxia-telangiectasia mutated (ATM) protein. A-T is characterised by immunodeficiency, reduced growth, insulin resistance and a predisposition to cancer. However, the hallmark symptom of ataxia, which presents within the first years of life, is caused by degeneration of cerebellar Purkinje and granule cells. At the cellular level, the loss of ATM leads to increased oxidative stress. The major function of ATM in normal cells is to activate DNA repair pathways in response to double strand breaks. However, the mechanisms leading to neurodegeneration of cerebellar Purkinje cells are still being elucidated. The focus of this study was to examine how oxidative stress contributes to defective cell signalling and the A-T phenotype. Examination of the insulin and epidermal (EGF) receptor signalling pathways by Western blotting indicated abnormal signalling in fibroblasts from A-T patients. Reduced expression of the membrane receptors and some effector proteins were a likely cause of the observed signalling defects. Fluorescence studies on transferrin receptor recycling identified delayed intracellular trafficking as a novel characteristic of the cellular A-T phenotype, and a contributing factor to altered signalling...