International Journal of Cell Biology by STI571 can decrease this translocation, impairing p53 accumulation in the nucleus of NPCs [32]. A redox imbalance is apparently a predominant feature of brains of individuals with Parkinson’s disease (PD). Evidence derived from postmortem studies indicates an increased oxidation of lipids, proteins and DNA, a severe decrease in GSH concentration, and an accumulation of SOD2 (see [33] and references therein). Oxidative DNA damage occurs to a higher extent in Parkinson’s disease individuals com- pared with age-matched controls [34]. Brains of Parkinson’s patients are also enriched in autophagosome-like structures reminiscent of autophagic stress. Interestingly, inherited forms of Parkinson’s disease are associated with loss-of- function mutations in genes encoding proteins that target the mitochondria and modulate autophagy, including the E3 ubiquitin ligase parkin (see [33] and references therein). c-Abl phosphorylates parkin on Y143 and inhibits parkin’s ubiquitin E3 ligase activity and its protective function. Conversely, STI-571 treatment prevents the phosphorylation of parkin, maintaining it in a catalytically active state. Inter- estingly, the protective eﬀect of STI-571 is not observed in parkin-deﬁcient cells. Conditional knockout of c-Abl also prevents the phosphorylation of parkin, the accumulation of its substrates, and results in neurotoxicity in response to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication [35]. Brieﬂy, STI-571 prevents tyrosine phos- phorylation of parkin and restores its E3 ligase activity and cytoprotective function both in vitro and in vivo. Compelling evidence indicates that tyrosine phosphorylation of parkin by c-Abl is a major posttranslational modiﬁcation that leads to loss of parkin function and disease progression in sporadic PD [36]. Moreover, a selective inhibition of c-Abl oﬀers new therapeutic strategies for blocking PD progression [35, 36]. Another level of c-Abl-dependent-regulation impinges on the activation of PKCδ. In cell culture models of PD, oxida- tive stress activates PKCδ through a caspase-3-dependent proteolytic cleavage inducing apoptotic cell death [37, 38]. Interestingly proteolytic activation of PKCδ is regulated through phosphorylation of its tyrosine residues [39]. Evi- dence regarding a functional interaction between PKCδ and c-Abl has been provided following oxidative stress response [14]. c-Abl phosphorylates PKCδ on tyrosine 311, with this modiﬁcation contributing to the apoptotic eﬀect of hydrogen peroxide [40]. On the other hand, ST571 can block PKCδ activation protecting cells from apoptosis [41]. Moreover, Xiao et al. identiﬁed c-Abl as a novel upstream activator of the protein kinase MST1 (mammalian Ste-20 like kinase1) that plays an essential role in oxidative-stress-induced neu- ronal cell death. Upon phosphorylation of MST1 at Y433 by c-Abl, authors demonstrated activation of FOXO3 that leads eventually to neuronal cell death. The latter mechanism is inhibited either by STI571 or c-Abl knockdown [42]. In short, this combined evidence stresses the physio- logical relevance of the interface between c-Abl signaling and redox state, metabolic regulation and DNA damage response mediated by transcription factors, such as FOXO- 3 or members of the p53 family. The dynamic of each signal-transduction path seems to be governed by a small set of recurring c-Abl-mediated 3 regulatory circuits, that depending on their subcellular localization and response duration may result in neuronal death (Figure 1). Of note, inactivation of c-Abl by STI571 can have a protective eﬀect and can reduce neuronal loss. 4. Autophagy, Mitochondria, and Oxidative Stress: Cross Talk with c-Abl Signaling Protein aggregation and organelle dysfunction are peculiar hallmarks of many late-onset neurodegenerative disorders. Mitochondrial damage and dysfunction is indeed linked to neurodegeneration in a variety of animal models [33]. Clearance of misfolded proteins and damaged organelles may be considered an eﬀective recovery strategy for stressed neuronal cells [43]. Autophagy is a lysosome-dependent pathway involved in the turnover of proteins and intra- cellular organelles. It is becoming increasingly evident that induction of a certain level of autophagy may exert a neuroprotective function, while its inappropriate or defective activation may result in neuronal cell loss in most neurode- generative diseases [44]. Abnormal autophagosomes are fre- quently observed in selective neuronal populations aﬄicted in common neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amy- otrophic lateral sclerosis. However, whether accumulation of autophagosomes plays a protective role or rather contributes to neuronal cell death is still a controversial issue [44, 45]. Despite this uncertainty, an accurate titration of autophagy should favor a neuroprotective response. In particular, if it is strictly modulated through an eﬃcient concerted action of the complex autophagy machinery. ROS can induce autophagy [46]. In addition, inhibition, depletion, or knock- out of the c-Abl family kinases, c-Abl and Arg, resulted in a dramatic reduction in the intracellular activities of the lyso- somal glycosidases alpha-galactosidase, alpha-mannosidase, and neuraminidase. Inhibition of c-Abl kinases also reduced the processing of the precursor forms of cathepsin D and cathepsin L to their mature, lysosomal forms, leading to an impaired turnover of long-lived cytosolic proteins and accumulation of autophagosomes [46, 47]. Together all these ﬁndings suggest a positive role for c-Abl kinases in the regula- tion of autophagy with important implications for therapies [46]. In conclusion, many observations indicate that c-Abl activity is increased in human neurodegenerative diseases (Alzheimer, Parkinson, and tauopathies). However, where c-Abl meets the cascade of events underlying neurodegen- erative disorders remains still elusive. A plausible scenario implies the involvement of c-Abl on multiple interconnected pathways eventually acting as an arbiter of neuronal survival and death decisions, most likely playing with autophagy, metabolic regulation and DNA damage signaling response. In adult mouse models, aberrant c-Abl activation causes neurodegeneration and neuroinﬂammation in forebrain neurons, thus implying c-Abl as a possible target for thera- peutic treatments [21]. Several reports have shown that c-Abl plays distinct roles based upon its subcellular localization. Is the achievement of a certain/speciﬁc relocalization of c- Abl required for the development of the neuronal disease?