title: p10, the N-terminal domain of p35, protects against CDK5/p25-induced neurotoxicity.
abstract: Cyclin-dependent kinase 5(CDK5) in complex with its activator, p35 (protein of 35 kDa), is essential for early neurodevelopment in mammals. However, endogenous cleavage of p35 to p25 is associated with neuron death and neurodegenerative disease. Here we show that a peptide (p10') encoding the N-terminal domain of p35 protects against CDK5/p25-induced toxicity in neurons. p10' also prevented the death of neurons treated with the neurotoxin, 1-methyl-4-phenylpyridinium (MPP(+)), which induces conversion of endogenous p35 to p25, and Parkinson disease (PD)-like symptoms in animals. MPP(+) induces CDK5/p25-dependent phosphorylation of peroxiredoxin 2 (Prx2), resulting in inhibition of its peroxireductase activity and accumulation of reactive oxygen species (ROS). We found that p10' expression inhibited both Prx2 phosphorylation and ROS accumulation in neurons. In addition, p10' inhibited the p25-induced appearance of antigen of the Ki67 antibody (Ki67) and phosphohistone H2AX (γH2AX), classic markers of cell cycle activity and DNA double-strand breakage, respectively, associated with neuron death. Our results suggest that p10 (protein of 10 kDa) is a unique prosurvival domain in p35, essential for normal CDK5/p35 function in neurons. Loss of the p10 domain results in CDK5/p25 toxicity and neurodegeneration in vivo.
authors.affiliation: Department of Molecular, Cellular and Developmental Biology and the Neuroscience Research Institute, University of California, Santa Barbara, CA 93106, USA.
authors.forename: Lingyan
authors.initials: L
authors.lastname: Zhang
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Karen K
authors.initials: KK
authors.lastname: Szumlinski
authors.forename: John
authors.initials: J
authors.lastname: Lew
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002522:Chlorocebus aethiops; D000090266:Chromobox Protein Homolog 5; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D007150:Immunohistochemistry; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D054464:Peroxiredoxins / Q000187:drug effects; D010766:Phosphorylation; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000715594:CBX5 protein, human; C500695:CDCA5 protein, human; C578016:Cdk5 activator fragment p10, human; D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C089495:neuronal Cdk5 activator (p25-p35); D000090266:Chromobox Protein Homolog 5; D054464:Peroxiredoxins; D051360:Cyclin-Dependent Kinase 5; C022616:thiazolyl blue; D015655:1-Methyl-4-phenylpyridinium