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Mount, Matthew P.,Zhang, Yi,Amini, Mandana,Callaghan, Steve,Kulczycki, Jerzy,Mao, Zixu,Slack, Ruth S.,Anisman, Hymie,Park, David S. American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.20
<P>We have earlier reported the critical nature of calpain-CDK5-MEF2 signaling in governing dopaminergic neuronal loss <I>in vivo</I>. CDK5 mediates phosphorylation of the neuronal survival factor myocyte enhancer factor 2 (MEF2) leading to its inactivation and loss. However, the downstream factors that mediate MEF2-regulated survival are unknown. Presently, we define <I>Nur77</I> as one such critical downstream survival effector. Following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment <I>in vivo</I>, <I>Nur77</I> expression in the nigrostriatal region is dramatically reduced. This loss is attenuated by expression of MEF2. Importantly, MEF2 constitutively binds to the <I>Nur77</I> promoter in neurons under basal conditions. This binding is lost following 1-methyl-4-phenylpyridinium treatment. <I>Nur77</I> deficiency results in significant sensitization to dopaminergic loss following 1-methyl-4-phenylpyridinium/MPTP treatment, <I>in vitro</I> and <I>in vivo</I>. Furthermore, <I>Nur77</I>-deficient MPTP-treated mice displayed significantly reduced levels of dopamine and 3,4-Dihydroxyphenylacetic acid in the striatum as well as elevated post synaptic FosB activity, indicative of increased nigrostriatal damage when compared with WT MPTP-treated controls. Importantly, this sensitization in <I>Nur77</I>-deficient mice was rescued with ectopic <I>Nur77</I> expression in the nigrostriatal system. These results indicate that the inactivation of <I>Nur77</I>, induced by loss of MEF2 activity, plays a critical role in nigrostriatal degeneration <I>in vivo</I>.</P>