2 in several cellular processes, including cell proliferation, cell cycle arrest, and programmed cell death [8]. Cellular responses to DNA damage or oxidative stress are critical for survival, and the direct link between ROS and oxidative DNA damage indicates the interplay of ROS signaling with the DNA damage response (DDR) [9]. Evidence indicates the involvement of the phosphatidylinositol-3-kinases- (PI3K-) related kinases, Ataxia telangiectasia mutated (ATM), DNA- dependent protein kinase catalytic subunit (DNA-PKcs), and ATM- and Rad-3 related (ATR) in oxidative DNA lesion repair and signaling response [10]. This ﬁnding together with the emerging role of c-Abl in the DDR [11] and in oxidative DNA damage [12] seems to point out a role for these DDR kinases as “sensors” for redox signaling. In particular, herein we discuss how an aberrant (nonspeciﬁc) c-Abl signaling may contribute to maintain high levels of ROS that in turn can damage organelles, mitochondria, and DNA, with these eﬀects ending towards neuronal degeneration. 2. ROS and c-Abl Signaling Oxidative stress contributes to the pathogenesis of a large number of human disorders. No doubt that a better under- standing of the controlled production (and of regulatory tar- gets) of ROS should provide the rationale for novel therapeu- tic treatments [13]. ROS signaling is reversible, tightly con- trolled through a regulatory network. This network results from a concerted assembly of protein complexes, built through protein interactions mediated by interaction mod- ules and posttranslational modiﬁcations in the binding partners. Protein modularity and the reversible nature of posttranslational modiﬁcations allow the dynamic assembly of local temporary signaling circuits regulated by feedback controls. The strength and the duration of redox signaling are regulated via the oxidative modiﬁcations of the kinases and phosphatases that in turn control the activity of enzymes involved in antioxidant activities and vice versa. Oxidant level modulates c-Abl activity [14, 15]. In turn, c-Abl can interact (and regulate) with several enzymes implicated in controlling the redox state of the cell. One of them, the catalase is an immediate eﬀector of the antioxidant cellular defense by converting H2O2 to H2O and O2 in the peroxi- somes. c-Abl and the product of the c-Abl-related gene (Arg) target catalase on the two residues Y321 and Y386 leading to its ubiquitination and to a consequent proteasomal- depend-ent degradation of the enzyme [16]. Similarly, c- Abl-deﬁcient cells display a higher level of expression of the antioxidant protein peroxiredoxin I (Prx1) [17]. Prx1 is con- sidered a physiological inhibitor of c-Abl. Prx1 interacts with the SH3 domain of c-Abl and inhibits its catalytic activity [18]. Depending on the oxidative level in the cell, glutathione peroxidase1 can be phosphorylated on Tyr-96 and activated by c-Abl/Arg [19]. In short, c-Abl activation has mostly a negative eﬀect on enzymes involved in the antioxidant defence, with rare exceptions. Moreover, c-abl, as a compo- nent of redox regulatory circuits, can be modiﬁed by S-glu- tathionylation, with this reversible modiﬁcation leading to downregulation of its kinase activity [20]. International Journal of Cell Biology 3. c-Abl Signaling in Neurodegenerative Disease Oxidative stress, accumulation of protein aggregates, and damaged mitochondria are common hallmarks of neurolog- ical diseases. Aberrant c-Abl activation is linked to many neuronal disorders as recently reviewed by Schlatterer and coworkers [21]. In the brain, c-Abl activation can be mon- itored by speciﬁc antibodies, which target phosphorylated residues present only in the active conformation of the kinase. Staining with these phosphoantibodies indicates that c-Abl colocalized with granulovacuolar degeneration (GVD) in brains of human Alzheimer (AD) patients. Moreover, c- Abl phosphorylated at T735, a site required for binding 14- 3-3 in the cytosol [22], colocalized with amyloid plaques, neuroﬁbrillary tangles (NFTs), and GVD in the entorhinal cortex and hippocampus and brain of AD patients [21, 23]. Tau phosphorylation mediated by c-Abl is detected in NFTs in Alzheimer disease [21, 24, 25]. Oxidative stress activates c-Abl in neuronal cells [26] and amyloid β results in increased expression of c-Abl and p73 [27]. Amyloid- β (Aβ) ﬁbrils in primary neurons induce the c-Abl/p73 proapoptotic signaling, while STI571, a pharmacological c- Abl inhibitor, prevents Amyloid β-dependent toxicity [26]. The c-Abl/p73 proapoptotic pathway is also targeted in the cerebellum of Niemann-Pick type C (NPC) mice [28]. Niemann-Pick type C (NPC) is a neurodegenerative disorder characterized by intralysosomal accumulation of cholesterol leading to neuronal loss. Pharmacological inhibition of c- Abl with STI571 rescues Purkinje neurons, reduces general cell apoptosis in the cerebellum, improves neurological symptoms, and increases the survival of NPC mice [29]. Evidence indicates that c-Abl binding with p73 is induced by ROS, with NAC (the oxidant scavenger N-acetylcysteine) treatment reducing the c-Abl/p73 activation as well as the levels of apoptosis in NPC neurons [28]. Recent ﬁndings indicate that some eﬀects of c-Abl induced by glucose metabolism might be mediated through p53 phosphorylation. In fact, c-Abl is involved in high glucose-induced apoptosis in embryonic E12.5 cortical neu- ral progenitor cells (NPCs) derived from mice brain. Once more again, inhibition of c-Abl by ST571 reduced apoptosis in NPCs by preventing the nuclear protein accumulation of p53 in response to high glucose [30]. Moreover, admin- istration of reactive oxygen species scavengers impairs the accumulation of c-Abl and p53 leading to a decreased NPCs apoptosis. In human neuroblastoma (SH-SY5Y) cells, c-Abl targets cyclin-dependent kinase 5 (Cdk5) on tyrosine residue Y15 in response to oxidative stress by hydrogen peroxide. In turn, Cdk5 can modulate p53 levels and p53 activity. Hence, both c-Abl and Cdk5 cooperatively mediate p53 transcriptional activation resulting in neuronal death [31]. A recent study also indicates that hyperglycemia-induced apoptosis of NPCs is mediated by a PKCδ- (Protein-Kinase C-delta-) dependent mechanism [32]. Tyrosine phosphory- lation of PKCδ by c-Abl is important for the translocation of the PKCδ-Abl complex from the cytoplasm to the nucleus. Downregulation of PKCδ (or c-Abl) or inhibition of c-Abl