title: CDK5 phosphorylates DRP1 and drives mitochondrial defects in NMDA-induced neuronal death.
abstract: Defects in mitochondrial fission and cyclin dependent kinase 5 (CDK5) activation are early events that precede neuronal loss following NMDA-induced neuronal death. Here, we report that the cytoplasmic CDK5 tightly regulates mitochondrial morphology defects associated with NMDA-induced neuronal injury via regulation of the mitochondrial fission protein, dynamin-related protein 1 (DRP1). We show that DRP1 is a direct target of CDK5. CDK5-mediated phosphorylation of DRP1 at a conserved Serine residue, S585, is elevated at the mitochondria and is associated with increased mitochondrial fission. Ectopic expression of a cytoplasmic CDK5 or mutant DRP1-S585D results in increased mitochondrial fragmentation in primary neurons. Conversely, expression of a dominant negative form of cytoplasmic CDK5 or mutant DRP1-S585A results in elongated mitochondria. In addition, pharmacological inhibition of CDK5 by Roscovitine inhibits DRP1 phosphorylation and mitochondrial fission associated with NMDA-induced neuronal loss. Importantly, conditional deletion of CDK5 significantly attenuates DRP1 phosphorylation at S585 and rescues mitochondrial fission defects in neurons exposed to NMDA. Our studies delineate an important mechanism by which CDK5 regulates mitochondrial morphology defects associated with neuronal injury.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5, Department of Oncology, Faculty of Medicine, McGill University and Lady Davis Institute at Jewish General Hospital, 3755 Ch de la Côte-Sainte-Catherine, Montréal QC, Canada H3T 1E2.
authors.forename: Arezu
authors.initials: A
authors.lastname: Jahani-Asl
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: En
authors.initials: E
authors.lastname: Huang
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5, Department of Ophthalmology, Queen's University and Hotel Dieu Hospital, Kingston, Ontario, Canada K7L 5G2 and.
authors.forename: Isabella
authors.initials: I
authors.lastname: Irrcher
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Juliet
authors.initials: J
authors.lastname: Rashidian
authors.affiliation: Department of Protein Biochemistry, Institute of Life Science, Kurume University, Kurume 839-0864, Japan.
authors.forename: Naotada
authors.initials: N
authors.lastname: Ishihara
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: Diane C
authors.initials: DC
authors.lastname: Lagace
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5, rslack@uottawa.ca dpark@uottawa.ca.
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.affiliation: Department of Cellular and Molecular Medicine, University of Ottawa Brain and Mind Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5, rslack@uottawa.ca dpark@uottawa.ca.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D034281:Dynamins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation
chemical_list: D016202:N-Methylaspartate; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins