Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP
Mutant Huntingtin Impairs BDNF Release from Astrocytes by Disrupting Conversion of Rab3a-GTP into Rab3a-GDP
复制标题
DOI：
10.1523/jneurosci.0168-16.2016
复制
发表时间：
2016-08-24
影响因子：
5.3
通讯作者：
Li, Shihua
中科院分区：
文献类型：
--
作者：
Hong, Yan;Zhao, Ting;Li, Shihua
脑源性神经营养因子（BDNF）对神经元的分化和存活至关重要。我们知道，亨廷顿氏病（HD）是一种由突变亨廷顿蛋白（mHtt）表达引起的神经退行性疾病，亨廷顿氏病（HD）患者的大脑中BDNF水平下降，而且在亨廷顿氏病小鼠中给予BDNF可以预防亨廷顿氏病的神经病理。BDNF在神经元中产生，但星形胶质细胞也是脑内BDNF的重要来源。尽管如此，mHtt是否影响HD脑中的星形细胞BDNF仍然未知。在这里，我们研究了HD140Q敲入小鼠的星形胶质细胞，发现mHtt减少星形胶质细胞分泌BDNF的证据，这是由星形胶质细胞胞吐介导的。我们的研究结果表明，mHtt与位于致密核囊泡膜上的小GTPase Rab3a结合，阻止GTP-Rab3a与Rab3-GAP1结合，破坏GTP-Rab3a向GDP-Rab3a的转化，从而损害BDNF囊泡在星形胶质细胞质膜上的对接。重要的是，Rab3a的过表达可以恢复HD星形胶质细胞中受损的BDNF囊泡对接和分泌。此外，HD星形胶质细胞中ATP的释放和含ATP的密核囊泡对接数量减少，表明mHtt损害了HD星形胶质细胞中密核囊泡的胞吐功能。此外，Rab3a过表达降低了HD140Q敲入小鼠纹状体中的反应性星形胶质细胞。我们的研究结果表明，HD星形胶质细胞中BDNF分泌受损导致HD脑中BDNF水平下降，并强调了改善胶质细胞功能在HD治疗中的重要性。
Brain-derived neurotrophic factor (BDNF) is essential for neuronal differentiation and survival. We know that BDNF levels decline in the brains of patients with Huntington's disease (HD), a neurodegenerative disease caused by the expression of mutant huntingtin protein (mHtt), and furthermore that administration of BDNF in HD mice is protective against HD neuropathology. BDNF is produced in neurons, but astrocytes are also an important source of BDNF in the brain. Nonetheless, whether mHtt affects astrocytic BDNF in the HD brain remains unknown. Here we investigated astrocytes from HD140Q knock-in mice and uncovered evidence that mHtt decreases BDNF secretion from astrocytes, which is mediated by exocytosis in astrocytes. Our results demonstrate that mHtt associates with Rab3a, a small GTPase localized on membranes of dense-core vesicles, and prevents GTP-Rab3a from binding to Rab3-GAP1, disrupting the conversion of GTP-Rab3a into GDP-Rab3a and thus impairing the docking of BDNF vesicles on plasma membranes of astrocytes. Importantly, overexpression of Rab3a rescues impaired BDNF vesicle docking and secretion from HD astrocytes. Moreover, ATP release and the number of ATP-containing dense-core vesicles docking are decreased in HD astrocytes, suggesting that the exocytosis of dense-core vesicles is impaired by mHtt in HD astrocytes. Further, Rab3a overexpression reduces reactive astrocytes in the striatum of HD140Q knock-in mice. Our results indicate that compromised exocytosis of BDNF in HD astrocytes contributes to the decreased BDNF levels in HD brains and underscores the importance of improving glial function in the treatment of HD.