Abstract
We have earlier reported the critical nature of calpain-CDK5-MEF2 signaling in governing dopaminergic neuronal loss in vivo. 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 Nur77 as one such critical downstream survival effector. Following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in vivo, Nur77 expression in the nigrostriatal region is dramatically reduced. This loss is attenuated by expression of MEF2. Importantly, MEF2 constitutively binds to the Nur77 promoter in neurons under basal conditions. This binding is lost following 1-methyl-4-phenylpyridinium treatment. Nur77 deficiency results in significant sensitization to dopaminergic loss following 1-methyl-4-phenylpyridinium/MPTP treatment, in vitro and in vivo. Furthermore, Nur77-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 Nur77-deficient mice was rescued with ectopic Nur77 expression in the nigrostriatal system. These results indicate that the inactivation of Nur77, induced by loss of MEF2 activity, plays a critical role in nigrostriatal degeneration in vivo.
Highlights
Nur77 expression is regulated by MEF2D, which is found to be associated with the calpain-CDK5-MEF2D neuronal death pathway
Nur77 Expression Following MPTP and Relationship with myocyte enhancer factor 2 (MEF2)—Our previous evidence indicated that loss of MEF2 activity, mediated by CDK5, was critical for dopaminergic loss induced by MPTP in vivo [7]
We assessed whether MEF2D binding on the endogenous Nur77 promoter may be affected by conditions that lead to neuronal loss using ChIP analysis
Summary
Nur expression is regulated by MEF2D, which is found to be associated with the calpain-CDK5-MEF2D neuronal death pathway. Nur Expression in Dopaminergic Neuron Survival was myocyte enhancer factor 2 (MEF2), a transcription factor with a critical role in muscle development [11], neuronal differentiation [12], and neuronal survival [13,14,15] In this regard, we observed calpain-mediated cleavage of p35 and consequent activation of CDK5 increased phosphorylation and inactivation of MEF2D in an MPTP model of dopamine degeneration in vivo [7]. A potential link between MEF2D and Nur in dopaminergic cell loss and the critical need to understand how MEF2 may regulate dopaminergic survival, and we examined whether Nur might be the mechanistic link driving a calpain-CDK5MEF2D-mediated pathway of death. We provide evidence that Nur is both regulated by CDK5-MEF2D and plays a critical role in the survival response to dopaminergic cell death
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