p10, the N-terminal domain of p35, protects against CDK5/p25-induced neurotoxicity
| Autor: | Wen Liu, John Lew, Karen K. Szumlinski, Lingyan Zhang |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
1-Methyl-4-phenylpyridinium
Cell Survival viruses Blotting Western Tetrazolium Salts Cell Cycle Proteins Nerve Tissue Proteins Peroxiredoxin 2 Biology Chlorocebus aethiops medicine Animals Neurotoxin Phosphorylation Adaptor Proteins Signal Transducing Neurons Multidisciplinary Kinase Cyclin-dependent kinase 5 Neurodegeneration Neurotoxicity Cyclin-Dependent Kinase 5 Peroxiredoxins Biological Sciences medicine.disease Immunohistochemistry Molecular biology Peptide Fragments Rats Cell biology Thiazoles Microscopy Fluorescence nervous system Chromobox Protein Homolog 5 COS Cells Proteolysis Peptides Reactive Oxygen Species Neuron death |
| Zdroj: | Proceedings of the National Academy of Sciences. 109:20041-20046 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1212914109 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|