title: 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).
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.
authors.affiliation: Department of Neuroscience and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Mount
authors.affiliation: Department of Neuroscience and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Mandana
authors.initials: M
authors.lastname: Amini
authors.affiliation: Department of Neuroscience and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Callaghan
authors.affiliation: Institute of Neuroscience, Carleton University, Ottawa, Ontario K1S 5B6, Canada.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kulczycki
authors.affiliation: Departments of Pharmacology and Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: Zixu
authors.initials: Z
authors.lastname: Mao
authors.affiliation: Department of Neuroscience and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.affiliation: Institute of Neuroscience, Carleton University, Ottawa, Ontario K1S 5B6, Canada.
authors.forename: Hymie
authors.initials: H
authors.lastname: Anisman
authors.affiliation: Department of Neuroscience and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada; Department of Cogno-Mechatronics Engineering, Pusan National University, Miryang 627-706, South Korea. Electronic address: dpark@uottawa.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D016923:Cell Death; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009498:Neurotoxins / Q000737:chemistry; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism
chemical_list: D064326:MEF2 Transcription Factors; C578044:Mef2d protein, mouse; D018006:Myogenic Regulatory Factors; D009498:Neurotoxins; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D015102:3,4-Dihydroxyphenylacetic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D002154:Calpain
keywords: Cdk5; Cell Death; Dopamine; MEF2; MPTP; Neurodegeneration; Neurotoxin; Nur77; Parkinson Disease
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