HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice.
HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice.
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DOI：
10.15252/emmm.201404392
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发表时间：
2015-01
影响因子：
11.1
通讯作者：
Okazawa H
中科院分区：
文献类型：
--
作者：
Ito H;Fujita K;Tagawa K;Chen X;Homma H;Sasabe T;Shimizu J;Shimizu S;Tamura T;Muramatsu S;Okazawa H
突变型ataxin-1(Atxn1)引起脊髓小脑型共济失调(SCA1)，它与高迁移率族蛋白1(HMGB1)结合并损害其功能，HMGB1是一种重要的核蛋白，调节DNA损伤修复和转录所必需的DNA结构变化。在这项研究中，我们证实了转基因或病毒载体介导的HMGB1互补可以改善突变的Atxn1基因敲入(Atxn1-ki)小鼠的运动功能障碍并延长其寿命。我们发现HMGB1的线粒体DNA损伤修复是这种作用的一个新的分子基础，除了与HMGB1功能相关的机制外，如核DNA损伤修复和核转录。线粒体DNA损伤修复功能的异常和改善分别与症状的加重和恢复密切相关，支持HMGB1对线粒体DNA质量的调控参与SCA1的病理过程。此外，我们还表明，HMGB1对浦肯野细胞树突棘和树突棘的挽救可能是下游效应。虽然细胞外HMGB1通过Toll样受体和晚期糖基化终末产物受体介导炎症，但细胞内HMGB1的上调不会引起这种副作用。因此，病毒传递HMGB1是一种即使在发病后也可以改变SCA1疾病进展的候选方法。
Mutant ataxin-1 (Atxn1), which causes spinocerebellar ataxia type 1 (SCA1), binds to and impairs the function of high-mobility group box 1 (HMGB1), a crucial nuclear protein that regulates DNA architectural changes essential for DNA damage repair and transcription. In this study, we established that transgenic or virus vector-mediated complementation with HMGB1 ameliorates motor dysfunction and prolongs lifespan in mutant Atxn1 knock-in (Atxn1-KI) mice. We identified mitochondrial DNA damage repair by HMGB1 as a novel molecular basis for this effect, in addition to the mechanisms already associated with HMGB1 function, such as nuclear DNA damage repair and nuclear transcription. The dysfunction and the improvement of mitochondrial DNA damage repair functions are tightly associated with the exacerbation and rescue, respectively, of symptoms, supporting the involvement of mitochondrial DNA quality control by HMGB1 in SCA1 pathology. Moreover, we show that the rescue of Purkinje cell dendrites and dendritic spines by HMGB1 could be downstream effects. Although extracellular HMGB1 triggers inflammation mediated by Toll-like receptor and receptor for advanced glycation end products, upregulation of intracellular HMGB1 does not induce such side effects. Thus, viral delivery of HMGB1 is a candidate approach by which to modify the disease progression of SCA1 even after the onset.
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影响因子：
3.5
作者：
Burright, EN;Davidson, JD;Orr, HT
通讯作者：
Orr, HT
影响因子：
16.2
作者：
Franco SJ;Martinez-Garay I;Gil-Sanz C;Harkins-Perry SR;Müller U
通讯作者：
Müller U
DOI：
10.1126/science.1212673
发表时间：
2011-11-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fryer JD;Yu P;Kang H;Mandel-Brehm C;Carter AN;Crespo-Barreto J;Gao Y;Flora A;Shaw C;Orr HT;Zoghbi HY
通讯作者：
Zoghbi HY
影响因子：
4.6
作者：
Iwata, Nobuhisa;Sekiguchi, Misaki;Hattori, Yoshino;Takahashi, Akane;Asai, Masashi;Ji, Bin;Higuchi, Makoto;Staufenbiel, Matthias;Muramatsu, Shin-ichi;Saido, Takaomi C.
通讯作者：
Saido, Takaomi C.
影响因子：
3.8
作者：
Lange SS;Reddy MC;Vasquez KM
通讯作者：
Vasquez KM