Oxidative Stress, DNA Damage, and c-Abl Signaling: At the Crossroad in Neurodegenerative Diseases?

Abstract

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.

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

“…Previous studies have demonstrated that c-Abl plays an essential role in PKCδ activation in response to oxidative stress (Gonfloni et al, 2012). In this context, c-Abl has been shown to phosphorylate PKCδ on tyrosine 311, which has been linked to apoptotic death in H 2 O 2 treated cells (Lu et al, 2007).…”

“…The ubiquitously expressed c-Abl is activated in response to diverse stimuli including growth factors, cell adhesion, oxidative stress and DNA damage (for a review see (Gonfloni et al, 2012)). Multiple lines of evidence document a role for c-Abl in oxidative stress-induced neuronal injury and high levels have been evidenced in postmortem PD brains (Ko et al, 2010; Brahmachari et al, 2016).…”

Inhibiting Tyrosine Phosphorylation of Protein Kinase Cδ (PKCδ) Protects the Salivary Gland from Radiation Damage

“…Our data support and extend previous studies that have reported a functional relationship between c-Abl and PKC␦ in response to genotoxic and oxidative stress (33)(34)(35). Both Yuan et al (34) and Sun et al (33) showed that hyperglycemia induced apoptosis of neural progenitor cells occurs through a PKC␦⅐c-Abl-dependent mechanism that involves tyrosine phosphorylation of PKC␦ and nuclear translocation of the PKC␦⅐c-Abl complex (36). Previous reports have demonstrated a role for members of the Src family of non-receptor tyrosine kinases in the regulation of PKC␦ (21,37,38).…”

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

“…While somatic mutations of PARK2 that decrease PARK2’s E3 ligase activity, compromising its ability to ubiquitinate cyclin E, are associated with cancer [121, 122], germline mutations of PARK2 were identified in patients with autosomal recessive juvenile Parkinsonism (ARJP) [123]. One of the main causes of PD is a redox imbalance in the brain [124]. Postmortem studies of PD patients reveal increased oxidation of lipids, proteins, and DNA, a severe decrease in glutathione concentration, and an accumulation of superoxide dismutase (SOD2) (reviewed in [125]).…”