Expression of mutant N-terminal huntingtin fragment (htt552-100Q) in astrocytes suppresses the secretion of BDNF
Expression of mutant N-terminal huntingtin fragment (htt552-100Q) in astrocytes suppresses the secretion of BDNF
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星形胶质细胞中突变型 N 末端亨廷顿蛋白片段 (htt552-100Q) 的表达抑制 BDNF 的分泌
DOI：
10.1016/j.brainres.2012.01.077
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发表时间：
2012-04
期刊：
影响因子：
2.9
通讯作者：
Qin, Zhenghong
中科院分区：
文献类型：
--
作者：
Wang, Linhui;Lin, Fang;Wang, Jin;Wu, Junchao;Han, Rong;Zhu, Lujia;DiFiglia, Marian;Qin, Zhenghong
亨廷顿氏病（HD）是一种遗传性神经系统疾病，由亨廷顿蛋白（htt）N-末端的多聚谷氨酰胺束的异常扩张引起。突变htt（mhtt）导致选择性神经变性，优先影响纹状体中型棘神经元。虽然mhtt也在星形胶质细胞中表达，但星形胶质细胞衍生的mhtt是否以及如何促成HD中的神经变性仍在很大程度上未知。在这项研究中，胶质细胞HD模型，使用腺病毒载体表达野生型和突变N-末端亨廷顿蛋白片段1 - 552 aa（htt552）在大鼠原代皮质星形胶质细胞，产生。观察htt552对星形胶质细胞脑源性神经营养因子（BDNF）蛋白水平的影响。免疫荧光显示，htt552 - 100Q在一些星形胶质细胞中形成聚集体。这些mhtt聚集体隔离网格蛋白免疫反应性和分散的高尔基复合体。ELISA和免疫荧光证实表达htt552 - 100Q的星形胶质细胞中BDNF水平增加。Westernblot分析显示，在表达htt552 - 100Q的星形胶质细胞中，pro-BDNF增加，而成熟BDNF减少。此外，从表达htt552 - 100Q的星形胶质细胞收集的培养基显示较低水平的成熟BDNF和较低的支持初级皮质神经元的神经突发育的活性。这些结果表明，突变体htt552形成的聚集体影响了星形胶质细胞对BDNF的加工和分泌，这可能有助于HD中神经元功能障碍和变性。
Huntington's disease (HD) is an inheritable neurological disorder caused by an abnormal expansion of the polyglutamine tract in the N-terminus of the protein huntingtin (htt). Mutant htt (mhtt) leads to selective neurodegeneration that preferentially affects striatal medium spiny neurons. Although mhtt is also expressed in astrocytes, whether and how astrocyte derived mhtt contributes to the neurodegeneration in HD remains largely unknown. In this study, a glia HD model, using an adenoviral vector to express wild-type and mutant N-terminal huntingtin fragment 1–552 aa (htt552) in rat primary cortical astrocytes, was generated. The influence of htt552 on the protein level of brain-derived neurotrophic factor (BDNF) in astrocytes was evaluated. Immunofluorescence showed that htt552-100Q formed aggregates in some astrocytes. These mhtt aggregates sequestered clathrin immunoreactivities and dispersed the Golgi complex. ELISA and immunofluorescence demonstrated an increase in BDNF levels in the astrocytes expressing htt552-100Q. Western blot analysis showed that there was an increase in pro-BDNF, but a decrease in mature BDNF in the astrocytes expressing htt552-100Q. Furthermore, medium collected from astrocytes expressing htt552-100Q showed a lower level of mature BDNF and less activity in supporting neurite development of primary cortical neurons. These results suggest that aggregates formed by mutant htt552 affect processing and secretion of the BDNF in astrocytes, which might contribute to the neuronal dysfunction and degeneration in HD.
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影响因子：
5.3
作者：
Canals, JM;Pineda, JR;Alberch, J
通讯作者：
Alberch, J
DOI：
10.1523/jneurosci.21-04-01257.2001
发表时间：
2001-02
期刊：
The Journal of Neuroscience
影响因子：
--
作者：
Y. Tokita;H. Keino;F. Matsui;S. Aono;H. Ishiguro;S. Higashiyama;A. Oohira
通讯作者：
Y. Tokita;H. Keino;F. Matsui;S. Aono;H. Ishiguro;S. Higashiyama;A. Oohira
影响因子：
4
作者：
W. Haubensak;F. Narz;R. Heumann;V. Lessmann
通讯作者：
W. Haubensak;F. Narz;R. Heumann;V. Lessmann
影响因子：
5.3
作者：
Sieradzan, KA;Mechan, AO;Mann, DMA
通讯作者：
Mann, DMA
影响因子：
16.2
作者：
DIFIGLIA, M;SAPP, E;ARONIN, N
通讯作者：
ARONIN, N