We discovered that percent of the flies demonstrated gentle fusion of the ommatidium with minimal fusion of the ommatidia

Moreover, deregulation of proteasome function induces c-Abl-mediated cell death, thus linking c-Abl to the proteasome system. Recently, we have identified the tyrosine phosphorylation of parkin by the oxidative stress-induced non-receptor tyrosine kinase c-Abl as a regulatory mechanism in parkin function. Parkin is tyrosine phosphorylated in the N-terminal domain by c-Abl, and Imatinib, a specific c-Abl kinase inhibitor used for treating chronic myeloid leukemia and gastrointestinal stromal tumors, inhibits that tyrosine phosphorylation. Tyrosine phosphorylation of parkin results in impaired E3-ubiquitin ligase activity and auto-ubiquitination of parkin. Imatinib, which is used in clinic as first line of treatment for chronic myeloid leukemia, is an effective c-Abl inhibitor and has a minimal capacity to cross blood-brain barrier, with an increase in the transport in the presence of radiation or Pglycoprotein and we examined mobile cycle distribution upon nutlin-3 treatment in cells was reduced by the use of a few diverse shRNA breast cancer resistance protein -inhibitors. However, it has not been shown to be effective in treating glioblastoma thus, opening a foray of development of second generation and brain permeable c-Abl inhibitors. One of the most selective and potent second-generation c-Abl inhibitor, INNO-406, has been shown to significantly enter brain and target glioblastoma. Here, we show that INNO-406 carries the potential to slow down the progression of PD thus becoming a very suitable target molecule for the development as a potential therapy for PD. One major attraction of repositioning INNO-406 for PD therapy is the fact that this drug has already been through extensive phase I and II studies and now entering into phase III trials for different type of leukemia. The c-Abl tyrosine kinase participates in a variety of cellular functions, including regulation of the actin cytoskeleton, regulation of the cell cycle, and the apoptotic/cell cycle arrest response to stress, and the Abl family of kinases has been shown to play a crucial role in development of the central nervous system. 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 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 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.

Latest comments

No comments