Recent studies have shown c-Abl activation in human Alzheimer��s and Parkinson��s diseases and c-Abl activation in mouse models and neuronal culture in response to amyloid beta fibrils and oxidative stress. Recently, we reported that oxidative and dopamine stresses lead to c-Abl activation, parkin tyrosine phosphorylation, and the consequent loss of parkin ubiquitination-dependent cytoprotective function. c-Abl-mediated parkin inactivation in response to oxidative and dopaminergic BMS 509744 stress seems to be the dominant pathway induced by these stressors, since the c-Abl inhibitor, Imatinib, blocked inactivation of parkin. Also, our finding that this pathway is seen predominantly in the striatum suggested that dopamine-containing cell types of the nigrostriatal pathway are particularly predisposed. c-Abl activation and tyrosine DSP-4 phosphorylation of parkin appear to reflect processes that are unique to the nigrostriatal pathway and not necessarily associated with inclusion bodies, since we did not observe c-Abl activation and tyrosine phosphorylation of parkin in the cortex, even in the four PD patients with neocortical Lewy bodies. The c-Abl inhibitor, Imatinib, is a widely used chemotherapeutic agent for chronic myelogenous leukemia. We have shown that Imatinib inhibits c-Abl��s deleterious effects on parkin by preventing its phosphorylation and preserving its protective function, held promise for further testing of this agent as a neuroprotective therapeutic for PD. Since Imatinib has limited brain bioavailability, the amount of protection afforded by inhibition of c-Abl in vivo may be greatly improved by using related compounds with enhanced brain penetration, as inhibition of c-Abl in cellular models is profoundly protective. INNO-406 is a second-generation tyrosine kinase inhibitor in development for treating Bcr-Abl+ leukemias, including chronic myelogenous leukemia and Philadelphia+ acute lymphoblastic leukemia. In preclinical studies, INNO-406 has been shown to be 25- to 55-fold more potent than Imatinib in vitro and $10- fold more potent in vivo. A significant fraction of INNO-406 crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Currently, INNO-406 is being developed in two phase II clinical trials for patients with Bcell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors. In our current studies, we show that INNO-406 significantly penetrates into the brain of mouse model of PD and prevents MPTP-induced activation of c-Abl and tyrosine phosphorylation of parkin. Furthermore, we show that INNO-406 very efficiently prevents dopaminergic neuronal and terminal damage and preserves dopamine content in the MPTP-mouse model of PD. Our results strengthen the data suggesting a role of parkin in the more common sporadic form of PD through oxidative stress, parkin phosphorylation, and the consequential loss of parkin ubiquitination and its protective function.