期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 87, 期 3, 页码 733-747出版社
WILEY-BLACKWELL
DOI: 10.1002/jnr.21881
关键词
Huntington's disease; DNA damage; neurodegeneration
资金
- Tapestry pharmaceuticals
Huntington's disease (HD) is a neurodegenerative disorder that follows an autosomal-dominant inheritance pattern. The pathogenesis of the disease depends on the degree of expansion of triplet (CAG) repeats located in the first exon on the gene. An expanded polyglutamine tract within the protein huntingtin (Htt) enables a gain-of-function phenotype that is often exhibited by a dysfunctional oligomerization process and the formation of protein aggregates. How this process leads to neurodegeneration remains undefined. We report that expression of a Htt-fragment containing an expanded glutamine tract induces DNA damage and activates the DNA damage response pathway. Both single-strand and double-strand breaks are observed as the mutant protein accumulates in the cell; these breaks precede the appearance of detectable protein aggregates containing mutant Htt. We also observe activation of H2AX, ATM, and p53 in cells expressing mutant Htt, a predictable response in cells containing chromosomal breakage. Expression of wild-type Htt does not affect the integrity of DNA, nor does it activate the same pathway. Furthermore, DNA damage and activated H2AX are present in HD transgenic mice before the formation of mutant Htt aggregates and HD pathogenesis. Taken together, our data suggest that the expression of mutant Htt causes an accumulation of DNA breaks that activates the DNA damage response pathway, a process that can disable cell function. Because these events can lead to apoptosis, it is possible that the DNA damage response pathway activated by single- and double-strand breaks that we found contributes to neurodegeneration. (C) 2008 Wiley-Liss, Inc.
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