Hindawi Publishing Corporation International Journal of Cell Biology Volume 2012, Article ID 683097, 7 pages doi:10.1155/2012/683097 Review Article Oxidative Stress, DNA Damage, and c-Abl Signaling: At the Crossroad in Neurodegenerative Diseases? Stefania Gonﬂoni,1 Emiliano Maiani,1 Claudia Di Bartolomeo,1 Marc Diederich,2 and Gianni Cesareni1 1 Department of Biology, University of Rome “Tor Vergata,” Via della Ricerca Scientiﬁca, 00133 Rome, Italy 2 Laboratoire de Biologie Mol´eculaire et Cellulaire du Cancer, Fondation de Recherche Cancer et Sang, Hoˆpital Kirchberg, 9 Rue Edward Steichen, 2540 Luxembourg, Luxembourg Correspondence should be addressed to Stefania Gonﬂoni, stefania.gonﬂoni@uniroma2.it Received 30 March 2012; Accepted 10 May 2012 Academic Editor: Pier Giorgio Mastroberardino Copyright © 2012 Stefania Gonﬂoni et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The c-Abl tyrosine kinase is implicated in diverse cellular activities including growth factor signaling, cell adhesion, oxidative stress, and DNA damage response. Studies in mouse models have shown that the kinases of the c-Abl family play a role in the development of the central nervous system. Recent reports show that aberrant c-Abl activation causes neuroinﬂammation and neuronal loss in the forebrain of transgenic adult mice. In line with these observations, an increased c-Abl activation is reported in human neurodegenerative pathologies, such as Parkinson’s, and Alzheimer’s diseases. This suggests that aberrant nonspeciﬁc posttranslational modiﬁcations induced by c-Abl may contribute to fuel the recurrent phenotypes/features linked to neurodegenerative disorders, such as an impaired mitochondrial function, oxidative stress, and accumulation of protein aggregates. Herein, we review some reports on c-Abl function in neuronal cells and we propose that modulation of diﬀerent aspects of c-Abl signaling may contribute to mediate the molecular events at the interface between stress signaling, metabolic regulation, and DNA damage. Finally, we propose that this may have an impact in the development of new therapeutic strategies. 1. Introduction A broad range of pathological disorders is linked to oxidative stress, including carcinogenesis and several age-dependent disorders (i.e., as neurodegenerative diseases). Oxidative stress is deﬁned as an imbalance in which the production of reactive oxygen species (ROS) overcomes the antioxidative cell defence system. Oxidative stress can be induced by exogenous and endogenous sources. For instance, hydrogen peroxide and chemotherapeutic reagents are exogenous sources of ROS, whereas mitochondrial energy metabolism is considered a major source for the production of ROS within the cell [1]. ROS can directly react with macromolecules, such as DNA, lipids, and proteins. Oxidative DNA lesions, if unrepaired, can induce mutations and deletions in both nuclear and mitochondrial genomes [2] and chromosomal abnormalities. Cells are also very sensitive to lipid peroxida- tion [3] and most amino acid residues in a protein can be oxidized by ROS. Often these modiﬁcations impair protein function [4]. Antioxidant defences are built in a complex network of nonenzymatic and enzymatic components of the cell. This network has been extensively reviewed [5, 6]. In short, Glutathione (GSH) is a nonenzymatic antioxidant, which acts in the cellular thiol/disulﬁde system, with the ratio of GSH to GSSH (glutathione disulphide) mirroring the redox status of the cell. On the other hand, enzymatic antioxidants include superoxide dismutases SODs, catalase, peroxiredoxins (PRxs), and glutathione peroxidases (GPx). The toxicity of ROS is only one facet of their action. ROS are also produced at low level within the cell, where they can play an important role in the redox-dependent regulation of signaling [7]. Hence, ROS are implicated