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Experimental evidence has demonstrated that, in PD conditions, over-activation of c-Abl might induce parkin dysfunction ( Imam et al., 2011 Gonfloni et al., 2012 Dawson and Dawson, 2014), a-synuclein aggregation ( Hebron et al., 2013a Mahul-Mellier et al., 2014 Brahmachari et al., 2016), and impaired autophagy of toxic elements ( Ertmer et al., 2007 Yogalingam and Pendergast, 2008 Xu et al., 2017), leading to the death of the nigral dopaminergic cells.
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There is an increase in the level and activity of c-Abl in human and mouse brains under PD conditions, which is evidently found in both the substantia nigra and striatum ( Ko et al., 2010 Imam et al., 2011, 2013 Hebron et al., 2013a Brahmachari et al., 2016). Observations from the past decade (for a review see, Brahmachari et al., 2017) indicate that impaired activity of c-Abl is implicated in the pathogenesis of Parkinson’s disease (PD), a neurodegenerative disorder caused by the progressive loss of dopamine (DA)-producing cells in the substantia nigra ( Lotharius and Brundin, 2002 Dauer and Przedborski, 2003 Lang and Espay, 2018). In the brain, under both normal and pathological conditions, c-Abl tyrosine kinase activity is linked to diverse neuronal functions related to cellular signaling ( Lee et al., 2008 Ko et al., 2010 Klein et al., 2011), synapse formation ( Finn et al., 2003 Perez de Arce et al., 2010 Vargas et al., 2014), and neurogenesis ( Moresco and Koleske, 2003 Woodring et al., 2003 Schlatterer et al., 2012). As c-Abl is highly conserved and ubiquitously expressed in multiple mammalian cellular and subcellular components, it likely plays a role in the regulation of a wide variety of biological processes ( Wang, 2014 Khatri et al., 2016).
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Future research is required to carefully evaluate the therapeutic efficacy and clinical challenges associated with applying c-Abl inhibitors to the treatment of PD.Ĭ-Abl (Abl1), also known as the Abelson murine leukemia viral oncogene homolog 1, is a member of the Abl family of non-receptor tyrosine kinases ( Colicelli, 2011). Based on this, we suggest that c-Abl inhibitors represent an ideal antiparkinsonian agent that has both disease-modifying and symptomatic effects.
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Moreover, in a series of studies, including that presented here, experimental evidence suggests that in a mouse model of parkinsonism induced by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, c-Abl inhibition exerts an immediate effect improving motor impairments by normalizing altered activity in striatal postsynaptic signaling pathways mediated by Cdk5 (cyclin-dependent kinase 5) and DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein 32 kDa). Accordingly, c-Abl inhibitors have been applied clinically as a disease-modifying therapeutic strategy for PD treatment. In the last decade, it has been observed that the inhibition of c-Abl activity holds promise for protection against the degeneration of nigral dopaminergic cells in PD and thereby exerts antiparkinsonian effects. An increase in the level and activity of the Abelson non-receptor tyrosine kinase (c-Abl) has been identified in both human and mouse brains under PD conditions. From the perspective of antiparkinsonian drug mechanisms, pharmacologic treatment of PD can be divided into symptomatic and disease-modifying (neuroprotective) therapies. Parkinson’s disease (PD) is caused by a progressive degeneration of nigral dopaminergic cells leading to striatal dopamine deficiency. 3Department of Medical Pharmacology, Institute of Biomedical Sciences, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima, Japan.2Department of Neurobiology and Therapeutics, Institute of Biomedical Sciences, Graduate School of Pharmaceutical Sciences, Tokushima University, Tokushima, Japan.1Department of Neurodegenerative Disorders Research, Institute of Biomedical Sciences, Graduate School of Medical Sciences, Tokushima University, Tokushima, Japan.Yu Zhou 1,2, Yukio Yamamura 1,2, Masatoshi Ogawa 1,2, Ryosuke Tsuji 1,2, Koichiro Tsuchiya 3, Jiro Kasahara 2 and Satoshi Goto 1*