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J Biol Chem, Vol. 273, Issue 44, 28873-28877, October 30, 1998
From the Department of Pharmaceutical Sciences, Northeastern
University, Boston, Massachusetts 02115
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.
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