Processing of cdk5 Activator p35 to Its Truncated Form (p25) by Calpain in Acutely Injured Neuronal Cells
| Autor: | Gerald P. Schielke, Albert W. Probert, Xiaodong Ren, Nancy C. Kupina, Megan Davis, Kevin K.W. Wang, Rathna Nath |
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| Rok vydání: | 2000 |
| Předmět: |
Male
Time Factors Blotting Western Lactacystin Biophysics Nerve Tissue Proteins tau Proteins Biochemistry Rats Sprague-Dawley chemistry.chemical_compound Enzyme activator medicine Animals Protein Isoforms Phosphorylation Molecular Biology Cells Cultured Cerebral Cortex Neurons Maitotoxin Dose-Response Relationship Drug biology Calpain Activator (genetics) Cyclin-dependent kinase 5 Oxocins Neurodegeneration Cell Biology medicine.disease Malonates Rats Cell biology Enzyme Activation nervous system chemistry Proteasome Reperfusion Injury Hypoxia-Ischemia Brain biology.protein Calcium Marine Toxins |
| Zdroj: | Biochemical and Biophysical Research Communications. 274:16-21 |
| ISSN: | 0006-291X |
| Popis: | Recently, it was shown that conversion of cdk5 activator protein p35 to a C-terminal fragment p25 promotes a deregulation of cdk5 activity, which may contribute to neurodegeneration in Alzheimer's disease. In this study, we present evidence that calpain is a protease involved in the conversion of p35 to p25. To activate calpain, rat cerebellar granule neurons were treated with maitotoxin (MTX). A C-terminus-directed anti-p35 antibody detected that p35 conversion to p25 paralleled the formation of calpain-generated alpha-spectrin (alpha-fodrin) breakdown products (SBDP's) in a maitotoxin-dose-dependent manner. Two calpain inhibitors (MDl28170 and SJA6017) reduced p35 processing but were unchanged when exposed to the caspase inhibitor carbobenzoxy-Asp-CH(2)OC(=O)-2, 6-dichlorobenzene or the proteasome inhibitors (lactacystin and Z-Ile-Glu(OtBu)Ala-Leu-CHO). p35 protein was also degraded to p25 when rat brain lysate was subjected to in vitro digestion with purified mu- and m-calpains. Additionally, in a rat temporary middle cerebral artery occlusion model, p35 processing to p25 again paralleled SBDP formation in the ischemic core. Lastly, in malonate-injured rat brains, the ipsilateral side showed a striking correlation of SBDP formation with p35 to p25 conversion and tau phosphorylation (at Ser202 and Thr205) increase. These data suggest that calpain is a major neuronal protease capable of converting p35 to p25 and might play a pathological role of activating cdk5 and its phosphorylation of tau in Alzheimer's disease. |
| Databáze: | OpenAIRE |
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