Perturbation of Transcription Factor Nur77 Expression Mediated by Myocyte Enhancer Factor 2D (MEF2D) Regulates Dopaminergic Neuron Loss in Response to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
| Autor: | David S. Park, Matthew P. Mount, Steve M. Callaghan, Mandana Amini, Jerzy Kulczycki, Zixu Mao, Yi Zhang, Ruth S. Slack, Hymie Anisman |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Mef2 Nerve growth factor IB Neurotoxins Substantia nigra Striatum Biology Biochemistry Mice chemistry.chemical_compound Neurobiology In vivo Nuclear Receptor Subfamily 4 Group A Member 1 Animals RNA Small Interfering Molecular Biology Mice Knockout Cell Death Calpain MEF2 Transcription Factors Dopaminergic Neurons MPTP Dopaminergic Brain Cyclin-Dependent Kinase 5 Cell Biology Molecular biology humanities Cell biology Substantia Nigra Gene Expression Regulation Myogenic Regulatory Factors nervous system chemistry 1-Methyl-4-phenyl-1 2 3 6-tetrahydropyridine 3 4-Dihydroxyphenylacetic Acid FOSB |
| Zdroj: | Journal of Biological Chemistry. 288:14362-14371 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m112.439216 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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