Expression of polyglutamine-expanded Huntingtin activates the SEK1-JNK pathway and induces apoptosis in a hippocampal neuronal cell line.
Huntington's disease is one of a growing number of hereditary neurodegenerative disorders caused by expansion of a polyglutamine stretch at the NH2 terminus of huntingtin. To explore whether polyglutamine-expanded huntingtin induces neuronal toxicity, I examined the expression of the full-length of huntingtin with 16, 48, or 89 polyglutamine repeats in a rat hippocampal neuronal cell (HN33). Expression of mutated huntingtin with 48 or 89 polyglutamine repeats stimulated c-Jun amino-terminal kinases (JNKs) activity and induced apoptotic cell death in HN33 cells while expression of normal huntingtin with 16 polyglutamine repeats had no toxic effect. The JNK activation precedes apoptotic cell death and co-expression of a dominant negative mutant form of stress-signaling kinase (SEK1) nearly completely blocked activation of JNKs and neuronal apoptosis mediated by mutated huntingtin. Taken together, my studies demonstrate that expression of polyglutamine-expanded huntingtin induces neuronal apoptosis via activation of the SEK1-JNK pathway.
Liu
Y F
YF
Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, USA.
D000818:Animals; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry*; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats
C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases