title: The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death.
abstract: Accumulating evidence suggests that deregulated cyclin-dependent kinase 5 (Cdk5) plays a critical part in neuronal death. However, the pathogenic targets of Cdk5 are not fully defined. Here we demonstrate that the Cdk5 activator p35 interacts directly with apurinic/apyrimidinic endonuclease 1 (Ape1), a protein crucial for base excision repair (BER) following DNA damage. Cdk5 complexes phosphorylate Ape1 at Thr 232 and thereby reduces its apurinic/apyrimidinic (AP) endonuclease activity. Ape1 phosphorylation is dependent on Cdk5 in in vitro and in vivo. The reduced endonuclease activity of phosphorylated Ape1 results in accumulation of DNA damage and contributes to neuronal death. Overexpression of Ape1(WT) and Ape1(T232A), but not the phosphorylation mimic Ape1(T232E), protects neurons against MPP(+)/MPTP. Loss of Ape1 sensitizes neurons to death. Importantly, increased phosphorylated Ape1 was also observed in post-mortem brain tissue from patients with Parkinson's and Alzheimer's diseases, suggesting a potential link between Ape1 phosphorylation and the pathogenesis of neurodegenerative diseases.
authors.affiliation: Cellular Molecular Medicine, Ottawa Hospital Research Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5.
authors.forename: En
authors.initials: E
authors.lastname: Huang
authors.forename: Dianbo
authors.initials: D
authors.lastname: Qu
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Katerina
authors.initials: K
authors.lastname: Venderova
authors.forename: M Emdadul
authors.initials: ME
authors.lastname: Haque
authors.forename: Maxime W C
authors.initials: MW
authors.lastname: Rousseaux
authors.forename: Ruth S
authors.initials: RS
authors.lastname: Slack
authors.forename: John M
authors.initials: JM
authors.lastname: Woulfe
authors.forename: David S
authors.initials: DS
authors.lastname: Park
mesh_terms: D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism* / Q000502:physiology; D004249:DNA Damage; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism* / Q000502:physiology; D004720:Endonucleases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: D051360:Cyclin-Dependent Kinase 5; D004720:Endonucleases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
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