突变亨廷顿蛋白对游离锌离子及其转运体ZnT3表达的影响及其机制研究
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摘要
亨廷顿舞蹈病(Huntington's disease, HD)是一种常染色体显性遗传性神经退行性疾病,由编码亨廷顿蛋白(huntingtin, Htt)的HD基因中CAG重复序列异常增多所致。临床上主要表现为运动失调、认知异常及精神障碍,病理学上以大脑皮质、纹状体等脑区神经元选择性丢失为特征。HD早期症状的出现与突触功能的异常有关,突变Htt对突触功能具有明显的毒性。
锌元素是人体内生命活动中必不可少的微量元素之一。人体内85%的锌离子通过与其结合蛋白结合而以结合形式存在,作为游离锌离子的一种储备形式,15%的锌离子以游离的形式存在。在脑内,约超过95%的游离锌离子存在于突触小泡内。在突触活动中,突触小泡内的游离锌离子与神经递质共同释放到突触间隙,参与调控多种突触后受体的功能,因此,锌离子稳态在突触传递调节中具有重要作用。
游离锌离子不能通过被动扩散通过细胞膜,其向细胞内外的转运依赖于锌离子转运体(zinc transporter)。锌离子转移转运体3(zinc transporter 3, ZnT3)与游离锌离子在突触小泡内的富集有关,细胞内ZnT3的表达水平影响细胞内游离锌离子的浓度。
在多种神经退行性疾病中均有脑内锌离子稳态紊乱,但HD脑内是否有游离锌离子水平的改变,突变Htt是否通过影响ZnT3的表达改变游离锌离子水平目前未见报道。
本研究利用HD转基因小鼠和转染表达突变Htt的细胞模型,观察了突变Htt对游离锌离子水平及ZnT3表达的影响及其机制,结果表明,突变Htt可通过影响Spl与ZnT3基因启动子序列的结合能力,下调ZnT3的表达,降低游离锌离子水平。
1.HD转基因小鼠脑内游离锌离子水平降低
为了观察突变Htt是否影响脑内锌离子水平,首先应用原子吸收分光光度法检测了HD转基因小鼠脑内锌元素总量。结果显示,与野生型(wild type, WT)小鼠比较,HD转基因(TG)小鼠脑皮质、纹状体和海马等脑区内的锌元素总量明显降低；应用游离锌离子金属自显影(AMG)技术对HD转基因小鼠脑内游离锌离子检测结果显示,TG小鼠中皮质、海马、纹状体、外侧苍白球、内侧苍白球和黑质等部位游离锌离子表达较WT小鼠相应脑区显著降低。由此提示,突变Htt可破坏脑内锌离子稳态并由此影响突触传递功能。
2.突变Htt下调ZnT3表达
脑组织内游离锌离子不能自由通过细胞膜,必须依靠锌离子转运体转运而进入细胞内。为了明确突变Htt是否通过影响ZnT3的表达使锌离子转运障碍而降低游离锌离子水平,对TG小鼠和HD细胞模型中ZnT3的表达水平进行了检测。免疫印迹检测显示,与WT小鼠比较,TG小鼠皮质、纹状体、海马等脑区的ZnT3表达在14周已经明显降低,在18周和20周降低更加明显；与转染正常Htt(20Q)的BHK细胞比较,转染突变Htt(160Q)的BHK细胞中ZnT3蛋白表达水平在转染24 h后降低,转染48 h和72 h后降低更为明显。RT-PCR检测显示,TG小鼠皮质、纹状体、海马等脑区和转染表达突变Htt的BHK细胞中ZnT3 mRNA水平的变化与蛋白水平变化一致。免疫组织化学检测结果显示,TG小鼠纹状体、外侧苍白球、内侧苍白球、黑质网状部、海马等脑区的ZnT3免疫反应性较WT小鼠相应区域明显减弱。以上结果提示,突变Htt可能通过抑制ZnT3基因转录而下调ZnT3的表达,突变Htt降低TG小鼠脑内游离锌离子水平的效应与其抑制ZnT3的表达而减少游离锌离子的转运有关。
3.Sp1调控ZnT3基因转录
突变Htt能通过影响转录因子的活性影响多种基因的转录。为了明确突变Htt是否通过影响调控ZnT3基因的转录因子活性抑制ZnT3基因的转录,对调控ZnT3基因的转录因子进行了分析。生物信息学分析显示,ZnT3基因启动子区域含有Sp1、WT1+KTS、WT1-KTS,、NF-κB p50 (NF-κB p50)、NF-κB p65等转录因子的可能结合基序,其中Sp1与NF-κB p65的评分较高。分别构建相关转录因子的质粒并转染BHK细胞后应用免疫印迹检测发现,在BHK细胞系中过表达Sp1对ZnT3的表达有上调作用,而过表达其它转录因子对ZnT3的表达无明显影响。进一步的免疫印迹和RT-PCR检测显示,在BHK细胞系中过表达Spl可使ZnT3的蛋白表达和(?)nRNA水平明显升高,而沉默Spl后,ZnT3的蛋白表达和mRNA水平则明显下调。双荧光素酶报告基因检测显示,过表达Spl后含pGL3-ZnT3(-283～+10)和pGL3-ZnT3(-193～+10)报告基因的荧光素酶活性明显升高,而含pGL3-ZnT3(-171～+10)报告基因的荧光素酶活性无改变。以上结果提示含有Spla和Splb的ZnT3基因启动子区(-184～-174bp)、(-269～-261bp)是Spl调控ZnT3基因转录的必须位点。而用染色质免疫共沉淀(Chromatin Imunoprecipitation, ChIP)技术检测出具有Spl作用基序的ZnT3基因启动子序列区片段能与Spl直接结合。这些结果提示Spl可与ZnT3基因启动子上的(-338～-232 bp)和(-253～-112 bp)基序结合来激活ZnT3基因的转录。
4.突变Htt抑制Spl与ZnT3基因启动子序列的结合
为了进一步证明突变Htt通过转录因子Spl抑制ZnT3基因的转录,将表达正常Htt的质粒(pJRed-20 Q-Htt)(?)(?)表达突变Htt的质粒(pJRed-160 Q-Htt)分别与ZnT3启动子中的(-283～+10 bp)片段克隆成的pGL3-basic荧光素酶报告基因质粒共转染BHK细胞后发现,突变Htt (pJRed-160 Q-Htt)使荧光素酶活性较对照组(pJRed-20Q-Htt)的荧光素酶活性较明显减弱,并呈浓度依赖性。而同时过表达外源性pEBGN-Spl和pJRed-160 Q-Htt质粒后的BHK细胞荧光素酶活性与同时过表达pJRed-20 Q-Htt和pEBGN空载质粒的BHK细胞荧光素酶活性相比无显著性差异,由此表明突变Htt可能通过抑制Spl的表达抑制ZnT3的转录。用RT-PCR和免疫印迹检测突变Htt对Spl mRNA和蛋白表达的影响后发现,TG小鼠脑组织中和表达pJRed-160 Q-Htt的BHK细胞中Sp1 mRNA和蛋白表达水平较WT小鼠和表达pJRed-20 Q-Htt的BHK细胞明显升高,TG小鼠脑组织Spl免疫反应性的免疫组织化学检测进一步证实,突变Htt可使Spl蛋白水平明显升高。因此,突变Htt不仅未抑制Spl的表达,反而对Spl的表达具有上调作用。为了解释在TG小鼠中Spl表达水平升高而其调控的下游基因ZnT3却表达下降这一现象,应用ChIP技术检测了突变Htt对Spl与ZnT3基因启动子结合能力的影响,结果表明,突变Htt使Spl与ZnT3基因启动子序列的结合能力明显减弱。
本研究结果表明,突变Htt通过抑制转录因子Sp1与ZnT3基因启动子的结合而抑制Sp1对ZnT3基因转录的激活作用,从而导致ZnT3基因的转录和表达下降,进而引起游离锌离子向突触小泡内的转运障碍,突触小泡内游离锌离子减少。突触小泡内游离锌离子减少将导致突触传递功能障碍。因此,本研究为揭示HD脑内突触传递功能障碍的机制提供了新的实验依据。
Huntington's disease (HD) is an autonomic, dominantly inherited neurological disorder caused by a CAG expansion within the coding sequence of HD gene, which results in a long stretch of polyglutamine of huntingtin. Clinically, Huntington's disease is characterized by irrepressible motor dysfunction, psychiatric disturbances and cognitive deterioration to dementia. The pathological characteristic feature of HD is the dramatic regional neurodegeneration in the brain, which occur most prominently in the striatumand deep layers of the cerebral cortex. Studies have suggested that mutant huntingtin (mHtt) can cause synaptic dysfunction by altering the availability of various synaptic proteins and formation aggregates in axonal terminals. Mutant huntingtin has the obvious toxicity to synaptic function.
Zinc is one of the essential trace elements in the biological functions of the mammals. Most of which zinc, about 85% of total content, is tightly bound to metalloenzymes where zinc is involved as a combination form and as the deposition of free zinc. A considerable amount of zinc, approximately 15% of total zinc is concentrated in synaptic vesicles as a pool of free or loosely bound zinc ions. Synaptic vesicles zinc, over 95% of free zinc exists in the synaptic vesicles, involved in synaptic transportation and synaptic activity. In synaptic activity, the zinc released into the synaptic cleft with other neurotransmitters and regulated receptors on the postsynaptic neurons. So the free zinc homeostasis has an important roal in the synaptic transmission.
The free zinc couldn't pass the membrane through the passive diffusion and the free zinc trafficking is mediated by zinc transporters (ZnTs). Previously results demonstrated that ZnT3 is required for transport of zinc into synaptic vesicles and suggest that vesicular zinc concentration is determined by the abundance of ZnT3.
Recent data have shown that vesicular Zinc, transported by ZnT3, was all changes in transgenic mice brainin of the neurodegenerative disease.However, free zinc and ZnT3 expression in HD have no reported. For this study, we characterized the association of mHtt with free zinc and its transporter ZnT3 and explored the mechanism of ZnT3 on the transcription dysfunction caused by mHtt. The results show that Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Spl to ZnT 3 promoter.
Decrease in level of free zinc in the brain of HD transgenic mice. To investigate the levels of total zinc element in the TG mice, metal content was measured by flame atomic absorption spectrometry. To compare with the WT mice, in the hippocampus cortex and striatum regions the zinc element was reduced significantly in the HD mice. To determine whether the vesicular zinc is affected in the TG mice, autometallography (AMG) staining method (sodium sulfide solution perfusion) was performed to stain the free zinc. Importantly, zinc density in the hippocampus, striatum, lateral globus pallidus and substantia nigra was reduced marked in the HD mice compared with WT mice. These results indicated that zinc homeostasis was damaged by the mHtt and then caused synaptic dysfunction.
Mutant Htt decreases expression of ZnT3. The free zinc couldn't pass the membrane through the passive diffusion. Studies have shown that vesicular zinc concentration is determined by the abundance of ZnT3. To investigate the ZnT3 mRNA and protein expression on the vesicle membranes, we performed the RT-PCR assay, immunohistochemical method and Western blotting analysis in the brain of TG mice and in the BHK cells transfected with pJRed-20 Q-Htt and pJRed-160 Q-Htt. Western blots analysis showed that the ZnT3 protein expression of cortex, hippocampus and striatum tissues from the 14W,18W and 20W HD mice was significantly reduced gradually compared with respectively WT mice. Moreover, the ZnT3 protein expression of the BHK cells transfected with pJRed-160 Q-Htt was decrease at the 24 h after the transfection and the 48 h and 72 h reduced seriously. Consistent with the ZnT3 protein expression, the mRNA level of ZnT3 in the HD mice and 160 Q/BHK cells was reduced marked. Immunohistochemical analysis observed that ZnT3 expression decreased in the hippocampus, striatum, medial and lateral globus pallidus and substantia nigra of TG mice at light-microscopic levels. Above results showed that the the mutant Htt suppressed the transcription of ZnT3 so that the free zinc and ZnT3 expression reduced significantly. Above results suggest that the free zinc levels reduced in the TG mice caused by the inhibition of the ZnT3 gene transcription disorders and expression reduced.
Sp1 activates transcription of ZnT3 gene. The mHtt has been shown to suppress the activities of many transcription factors and-subsequently causes transcriptional dysfunction. To further explore the mechanism of ZnT3 mRNA suppression on the above results, we have to find out which ones were the transcription factors of ZnT3 gene. Bioinformatics analysis showed that the ZnT3 gene promoter region contains Spl, WT1+ KTS, WT1-KTS, NF-κB in p50, NF-κB of p65 and other transcription factors may be binding with the ZnT3 promoter sequence, in which the Sp1 has a higher score than the others. Western blot detection showed that over-expression of Sp1 to upregulate the expression of ZnT3 in the BHK cell lines and the other ranscription factors have no this effection on the expression of ZnT3. Furthermore, we found that ZnT3 expression increased after the BHK cells transfected with pEBGN-Sp1 and decreased after the Sp1 RNA inteference applied in BHK cells. According to the ZnT3 promoter sequence, there were two conserved Sp1 binding site (-269bp～-261bp,-184bp～-174bp) were named Spla and Splb. Dual Luciferase Reporter Gene Assay showed that pEBGN-Spl over-expression enhanced the pGL3-ZnT3(-283-+10) and pGL3-ZnT3(-193～+10) promoter activity. The ChIP results revealed that Spl is one of the transcriptional factors and Sp1 can combine with the ZnT3 promoter sequences at Sp1a and Sp1b sites directly.
Mutant huntingtin reduces binding of Sp1 to ZnT3 promoter sequence. To investigate whether the mHtt suppress the ZnT3 expression by reducing the activity of ZnT3 promoter,we construct the plasmid of pGL3-ZnT3(-283～+10). And then,we inspected the dual luciferase activity after the co-transfected pJRed-160 Q-Htt and PGL3-ZnT3(-283～+10bp) in the BHK cells for 48 h. When compared the dual luciferase activity of cells transfected pJRed-160 Q-Htt at the different does with the cells transfected with pJRed-20 Q-Htt, the value was less gradually and the decrease tendency was does depended. The mHtt appeared to inhibit the expression of ZnT3 at the transcription level in BHK cells. We also co-transfected the Spl-pEBGN and ZnT3 promoter construct with different does of pJRed-20 Q-Htt or pJRed-160 Q-Htt in the BHK cells. Thus the results showed that the ZnT3 promoter sequence dual luciferase activity of co-transfected with pJRed-160 Q-Htt and Spl-pEBGN was corrected compared with co-transfected with pJRed-160 Q-Htt and pEBGN vector. Furthermore, we have inspected transcriptional inhibition of the ZnT3 gene by mHtt and the rectification by 160 Q and Spl co-transfected in BHK cells. To explore the paradox of Spl-driven gene ZnT3 transcription suppression and the Spl expression increased in the TG mcie and BHK/160 Q cells, we performed the ChIP assay to it. Having revealed specificity of the ChIP technique, we sought to compare the binding of Spl to the ZnT3 promoter in BHK/160 Q cells to BHK/20 Q control cells. Sp1a and Sp1b sites of Spl combined with in the ZnT3 promoter sequence, were amplified 106bp and 141bp. RT-PCR results showed that the both of ZnT3 promoter sequence bands in BHK/160 Q cells were weaker than in the BHK/20 Q control cells.The difference indicates that there was less Spl associated with the ZnT3 promoter in BHK/160 Q cells as compared to the BHK/20 Q control cells. The decreases of Spl binding to target gene ZnT3 explained the previous results of decreased overall level of ZnT3 and increased overall of Spl.
The results of this study showed that the mHtt inhibit the combination of transcription factor Spl and ZnT3 gene promoter sequence, resulting in the ZnT3 gene transcription and expression decreased and then free zinc level in the synaptic vesicles suppression and synaptic dysfunction. This study provides a new experimental basis to reveal the mechanism of HD synaptic transmission and synaptic dysfunction.
锌元素是人体内生命活动中必不可少的微量元素之一。人体内85%的锌离子通过与其结合蛋白结合而以结合形式存在,作为游离锌离子的一种储备形式,15%的锌离子以游离的形式存在。在脑内,约超过95%的游离锌离子存在于突触小泡内。在突触活动中,突触小泡内的游离锌离子与神经递质共同释放到突触间隙,参与调控多种突触后受体的功能,因此,锌离子稳态在突触传递调节中具有重要作用。
游离锌离子不能通过被动扩散通过细胞膜,其向细胞内外的转运依赖于锌离子转运体(zinc transporter)。锌离子转移转运体3(zinc transporter 3, ZnT3)与游离锌离子在突触小泡内的富集有关,细胞内ZnT3的表达水平影响细胞内游离锌离子的浓度。
在多种神经退行性疾病中均有脑内锌离子稳态紊乱,但HD脑内是否有游离锌离子水平的改变,突变Htt是否通过影响ZnT3的表达改变游离锌离子水平目前未见报道。
本研究利用HD转基因小鼠和转染表达突变Htt的细胞模型,观察了突变Htt对游离锌离子水平及ZnT3表达的影响及其机制,结果表明,突变Htt可通过影响Spl与ZnT3基因启动子序列的结合能力,下调ZnT3的表达,降低游离锌离子水平。
1.HD转基因小鼠脑内游离锌离子水平降低
为了观察突变Htt是否影响脑内锌离子水平,首先应用原子吸收分光光度法检测了HD转基因小鼠脑内锌元素总量。结果显示,与野生型(wild type, WT)小鼠比较,HD转基因(TG)小鼠脑皮质、纹状体和海马等脑区内的锌元素总量明显降低；应用游离锌离子金属自显影(AMG)技术对HD转基因小鼠脑内游离锌离子检测结果显示,TG小鼠中皮质、海马、纹状体、外侧苍白球、内侧苍白球和黑质等部位游离锌离子表达较WT小鼠相应脑区显著降低。由此提示,突变Htt可破坏脑内锌离子稳态并由此影响突触传递功能。
2.突变Htt下调ZnT3表达
脑组织内游离锌离子不能自由通过细胞膜,必须依靠锌离子转运体转运而进入细胞内。为了明确突变Htt是否通过影响ZnT3的表达使锌离子转运障碍而降低游离锌离子水平,对TG小鼠和HD细胞模型中ZnT3的表达水平进行了检测。免疫印迹检测显示,与WT小鼠比较,TG小鼠皮质、纹状体、海马等脑区的ZnT3表达在14周已经明显降低,在18周和20周降低更加明显；与转染正常Htt(20Q)的BHK细胞比较,转染突变Htt(160Q)的BHK细胞中ZnT3蛋白表达水平在转染24 h后降低,转染48 h和72 h后降低更为明显。RT-PCR检测显示,TG小鼠皮质、纹状体、海马等脑区和转染表达突变Htt的BHK细胞中ZnT3 mRNA水平的变化与蛋白水平变化一致。免疫组织化学检测结果显示,TG小鼠纹状体、外侧苍白球、内侧苍白球、黑质网状部、海马等脑区的ZnT3免疫反应性较WT小鼠相应区域明显减弱。以上结果提示,突变Htt可能通过抑制ZnT3基因转录而下调ZnT3的表达,突变Htt降低TG小鼠脑内游离锌离子水平的效应与其抑制ZnT3的表达而减少游离锌离子的转运有关。
3.Sp1调控ZnT3基因转录
突变Htt能通过影响转录因子的活性影响多种基因的转录。为了明确突变Htt是否通过影响调控ZnT3基因的转录因子活性抑制ZnT3基因的转录,对调控ZnT3基因的转录因子进行了分析。生物信息学分析显示,ZnT3基因启动子区域含有Sp1、WT1+KTS、WT1-KTS,、NF-κB p50 (NF-κB p50)、NF-κB p65等转录因子的可能结合基序,其中Sp1与NF-κB p65的评分较高。分别构建相关转录因子的质粒并转染BHK细胞后应用免疫印迹检测发现,在BHK细胞系中过表达Sp1对ZnT3的表达有上调作用,而过表达其它转录因子对ZnT3的表达无明显影响。进一步的免疫印迹和RT-PCR检测显示,在BHK细胞系中过表达Spl可使ZnT3的蛋白表达和(?)nRNA水平明显升高,而沉默Spl后,ZnT3的蛋白表达和mRNA水平则明显下调。双荧光素酶报告基因检测显示,过表达Spl后含pGL3-ZnT3(-283～+10)和pGL3-ZnT3(-193～+10)报告基因的荧光素酶活性明显升高,而含pGL3-ZnT3(-171～+10)报告基因的荧光素酶活性无改变。以上结果提示含有Spla和Splb的ZnT3基因启动子区(-184～-174bp)、(-269～-261bp)是Spl调控ZnT3基因转录的必须位点。而用染色质免疫共沉淀(Chromatin Imunoprecipitation, ChIP)技术检测出具有Spl作用基序的ZnT3基因启动子序列区片段能与Spl直接结合。这些结果提示Spl可与ZnT3基因启动子上的(-338～-232 bp)和(-253～-112 bp)基序结合来激活ZnT3基因的转录。
4.突变Htt抑制Spl与ZnT3基因启动子序列的结合
为了进一步证明突变Htt通过转录因子Spl抑制ZnT3基因的转录,将表达正常Htt的质粒(pJRed-20 Q-Htt)(?)(?)表达突变Htt的质粒(pJRed-160 Q-Htt)分别与ZnT3启动子中的(-283～+10 bp)片段克隆成的pGL3-basic荧光素酶报告基因质粒共转染BHK细胞后发现,突变Htt (pJRed-160 Q-Htt)使荧光素酶活性较对照组(pJRed-20Q-Htt)的荧光素酶活性较明显减弱,并呈浓度依赖性。而同时过表达外源性pEBGN-Spl和pJRed-160 Q-Htt质粒后的BHK细胞荧光素酶活性与同时过表达pJRed-20 Q-Htt和pEBGN空载质粒的BHK细胞荧光素酶活性相比无显著性差异,由此表明突变Htt可能通过抑制Spl的表达抑制ZnT3的转录。用RT-PCR和免疫印迹检测突变Htt对Spl mRNA和蛋白表达的影响后发现,TG小鼠脑组织中和表达pJRed-160 Q-Htt的BHK细胞中Sp1 mRNA和蛋白表达水平较WT小鼠和表达pJRed-20 Q-Htt的BHK细胞明显升高,TG小鼠脑组织Spl免疫反应性的免疫组织化学检测进一步证实,突变Htt可使Spl蛋白水平明显升高。因此,突变Htt不仅未抑制Spl的表达,反而对Spl的表达具有上调作用。为了解释在TG小鼠中Spl表达水平升高而其调控的下游基因ZnT3却表达下降这一现象,应用ChIP技术检测了突变Htt对Spl与ZnT3基因启动子结合能力的影响,结果表明,突变Htt使Spl与ZnT3基因启动子序列的结合能力明显减弱。
本研究结果表明,突变Htt通过抑制转录因子Sp1与ZnT3基因启动子的结合而抑制Sp1对ZnT3基因转录的激活作用,从而导致ZnT3基因的转录和表达下降,进而引起游离锌离子向突触小泡内的转运障碍,突触小泡内游离锌离子减少。突触小泡内游离锌离子减少将导致突触传递功能障碍。因此,本研究为揭示HD脑内突触传递功能障碍的机制提供了新的实验依据。
Huntington's disease (HD) is an autonomic, dominantly inherited neurological disorder caused by a CAG expansion within the coding sequence of HD gene, which results in a long stretch of polyglutamine of huntingtin. Clinically, Huntington's disease is characterized by irrepressible motor dysfunction, psychiatric disturbances and cognitive deterioration to dementia. The pathological characteristic feature of HD is the dramatic regional neurodegeneration in the brain, which occur most prominently in the striatumand deep layers of the cerebral cortex. Studies have suggested that mutant huntingtin (mHtt) can cause synaptic dysfunction by altering the availability of various synaptic proteins and formation aggregates in axonal terminals. Mutant huntingtin has the obvious toxicity to synaptic function.
Zinc is one of the essential trace elements in the biological functions of the mammals. Most of which zinc, about 85% of total content, is tightly bound to metalloenzymes where zinc is involved as a combination form and as the deposition of free zinc. A considerable amount of zinc, approximately 15% of total zinc is concentrated in synaptic vesicles as a pool of free or loosely bound zinc ions. Synaptic vesicles zinc, over 95% of free zinc exists in the synaptic vesicles, involved in synaptic transportation and synaptic activity. In synaptic activity, the zinc released into the synaptic cleft with other neurotransmitters and regulated receptors on the postsynaptic neurons. So the free zinc homeostasis has an important roal in the synaptic transmission.
The free zinc couldn't pass the membrane through the passive diffusion and the free zinc trafficking is mediated by zinc transporters (ZnTs). Previously results demonstrated that ZnT3 is required for transport of zinc into synaptic vesicles and suggest that vesicular zinc concentration is determined by the abundance of ZnT3.
Recent data have shown that vesicular Zinc, transported by ZnT3, was all changes in transgenic mice brainin of the neurodegenerative disease.However, free zinc and ZnT3 expression in HD have no reported. For this study, we characterized the association of mHtt with free zinc and its transporter ZnT3 and explored the mechanism of ZnT3 on the transcription dysfunction caused by mHtt. The results show that Mutant huntingtin reduces vesicular zinc level by inhibiting the binding of Spl to ZnT 3 promoter.
Decrease in level of free zinc in the brain of HD transgenic mice. To investigate the levels of total zinc element in the TG mice, metal content was measured by flame atomic absorption spectrometry. To compare with the WT mice, in the hippocampus cortex and striatum regions the zinc element was reduced significantly in the HD mice. To determine whether the vesicular zinc is affected in the TG mice, autometallography (AMG) staining method (sodium sulfide solution perfusion) was performed to stain the free zinc. Importantly, zinc density in the hippocampus, striatum, lateral globus pallidus and substantia nigra was reduced marked in the HD mice compared with WT mice. These results indicated that zinc homeostasis was damaged by the mHtt and then caused synaptic dysfunction.
Mutant Htt decreases expression of ZnT3. The free zinc couldn't pass the membrane through the passive diffusion. Studies have shown that vesicular zinc concentration is determined by the abundance of ZnT3. To investigate the ZnT3 mRNA and protein expression on the vesicle membranes, we performed the RT-PCR assay, immunohistochemical method and Western blotting analysis in the brain of TG mice and in the BHK cells transfected with pJRed-20 Q-Htt and pJRed-160 Q-Htt. Western blots analysis showed that the ZnT3 protein expression of cortex, hippocampus and striatum tissues from the 14W,18W and 20W HD mice was significantly reduced gradually compared with respectively WT mice. Moreover, the ZnT3 protein expression of the BHK cells transfected with pJRed-160 Q-Htt was decrease at the 24 h after the transfection and the 48 h and 72 h reduced seriously. Consistent with the ZnT3 protein expression, the mRNA level of ZnT3 in the HD mice and 160 Q/BHK cells was reduced marked. Immunohistochemical analysis observed that ZnT3 expression decreased in the hippocampus, striatum, medial and lateral globus pallidus and substantia nigra of TG mice at light-microscopic levels. Above results showed that the the mutant Htt suppressed the transcription of ZnT3 so that the free zinc and ZnT3 expression reduced significantly. Above results suggest that the free zinc levels reduced in the TG mice caused by the inhibition of the ZnT3 gene transcription disorders and expression reduced.
Sp1 activates transcription of ZnT3 gene. The mHtt has been shown to suppress the activities of many transcription factors and-subsequently causes transcriptional dysfunction. To further explore the mechanism of ZnT3 mRNA suppression on the above results, we have to find out which ones were the transcription factors of ZnT3 gene. Bioinformatics analysis showed that the ZnT3 gene promoter region contains Spl, WT1+ KTS, WT1-KTS, NF-κB in p50, NF-κB of p65 and other transcription factors may be binding with the ZnT3 promoter sequence, in which the Sp1 has a higher score than the others. Western blot detection showed that over-expression of Sp1 to upregulate the expression of ZnT3 in the BHK cell lines and the other ranscription factors have no this effection on the expression of ZnT3. Furthermore, we found that ZnT3 expression increased after the BHK cells transfected with pEBGN-Sp1 and decreased after the Sp1 RNA inteference applied in BHK cells. According to the ZnT3 promoter sequence, there were two conserved Sp1 binding site (-269bp～-261bp,-184bp～-174bp) were named Spla and Splb. Dual Luciferase Reporter Gene Assay showed that pEBGN-Spl over-expression enhanced the pGL3-ZnT3(-283-+10) and pGL3-ZnT3(-193～+10) promoter activity. The ChIP results revealed that Spl is one of the transcriptional factors and Sp1 can combine with the ZnT3 promoter sequences at Sp1a and Sp1b sites directly.
Mutant huntingtin reduces binding of Sp1 to ZnT3 promoter sequence. To investigate whether the mHtt suppress the ZnT3 expression by reducing the activity of ZnT3 promoter,we construct the plasmid of pGL3-ZnT3(-283～+10). And then,we inspected the dual luciferase activity after the co-transfected pJRed-160 Q-Htt and PGL3-ZnT3(-283～+10bp) in the BHK cells for 48 h. When compared the dual luciferase activity of cells transfected pJRed-160 Q-Htt at the different does with the cells transfected with pJRed-20 Q-Htt, the value was less gradually and the decrease tendency was does depended. The mHtt appeared to inhibit the expression of ZnT3 at the transcription level in BHK cells. We also co-transfected the Spl-pEBGN and ZnT3 promoter construct with different does of pJRed-20 Q-Htt or pJRed-160 Q-Htt in the BHK cells. Thus the results showed that the ZnT3 promoter sequence dual luciferase activity of co-transfected with pJRed-160 Q-Htt and Spl-pEBGN was corrected compared with co-transfected with pJRed-160 Q-Htt and pEBGN vector. Furthermore, we have inspected transcriptional inhibition of the ZnT3 gene by mHtt and the rectification by 160 Q and Spl co-transfected in BHK cells. To explore the paradox of Spl-driven gene ZnT3 transcription suppression and the Spl expression increased in the TG mcie and BHK/160 Q cells, we performed the ChIP assay to it. Having revealed specificity of the ChIP technique, we sought to compare the binding of Spl to the ZnT3 promoter in BHK/160 Q cells to BHK/20 Q control cells. Sp1a and Sp1b sites of Spl combined with in the ZnT3 promoter sequence, were amplified 106bp and 141bp. RT-PCR results showed that the both of ZnT3 promoter sequence bands in BHK/160 Q cells were weaker than in the BHK/20 Q control cells.The difference indicates that there was less Spl associated with the ZnT3 promoter in BHK/160 Q cells as compared to the BHK/20 Q control cells. The decreases of Spl binding to target gene ZnT3 explained the previous results of decreased overall level of ZnT3 and increased overall of Spl.
The results of this study showed that the mHtt inhibit the combination of transcription factor Spl and ZnT3 gene promoter sequence, resulting in the ZnT3 gene transcription and expression decreased and then free zinc level in the synaptic vesicles suppression and synaptic dysfunction. This study provides a new experimental basis to reveal the mechanism of HD synaptic transmission and synaptic dysfunction.
引文
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