Molecular mechanisms of neurodegeneration

神经退行性变的分子机制

• 批准号: 12210008
• 负责人: TSUJI Shoji
• 金额: $ 156.29万
• 依托单位: The University of Tokyo (2002-2004)Niigata University (2000-2001)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12210008/
• 关键词: polyglutamine diseases; nuclear accumulation; transcriptional dysregulation; cAMP-responsive gene; CREB-dependent transcriptional activation; expression profiling; dentatorubral-pallidoluysian atrophy; CAG repeat; 歯状核赤核・淡倉球ルイ体萎縮症; neurodegenerati

To date, 9 polyglutamine diseases including dentatorubral-pallidoluysian atrophy (DRPLA) have been identified to be caused by abnormal expansion of CAG repeats coding for polyglutamine stretches. To elucidate the molecular mechanisms of neurodegeneration in polyglutamine diseases, we first attempted to create mouse models that closely replicate pathophysiologic processes in human brains. To accomplish this aim, we tried to create transgenic mice carrying a full-length mutant human DRPLA gene as a single copy gene. The Q129 mouse carrying a largely expanded CAG repeats (129) showed strong neurological phenotypes including ataxia, myoclonus and epilepsy. Based on detailed neuropathological analyses, we found that neuronal loss was not detected despite the strong phenotypes, suggesting that neuronal death is not the essential processes in neurodegeneration. We furthermore found that intranuclear accumulation of mutant DRPLA proteins is the essential neuropathological findings. This observ … More ation raises the possibility that nuclear dysfunction underlies the neurodegeneration in polyglutamine diseases. Based on cell culture systems, we demonstrated that CREB-dependent transcriptional activation is severely suppressed employing a reporter system. We further demonstrated activation of endogenous c-fos transcription is also strongly suppressed by expanded polyglutamine stretches. To further elucidate the mechanisms of transcriptional dysregulation in polyglutamine diseases, we have conducted detailed expression profiling analyses using Q76, Q113 and Q129, carrying a full-length mutant human DRPLA gene as a single copy gene with various lengths of expanded CAG repeats (76, 113 and 129 repeat units). We found that substantial number of genes were suppressed in time-dependent and repeat length-dependent manners. Among the down-regulated genes, many cAMP-responsive genes (c-fos and EGR1) are included Taken together, we have demonstrated that suppression of CREB-dependent transcriptional activation is strongly suppressed by expanded polyglutamine stretches and restoration of such suppression is the target for developing therapeutic approaches for polyglutamine diseases. Less

到目前为止，包括齿状核-苍白球萎缩在内的9种聚谷氨酰胺病已被证实是由编码聚谷氨酰胺片段的CAG重复序列的异常扩张引起的。为了阐明聚谷氨酰胺疾病中神经退行性变的分子机制，我们首先试图创建紧密复制人脑病理生理过程的小鼠模型。为了实现这一目标，我们试图创造携带全长突变的人DRLA基因作为单拷贝基因的转基因小鼠。携带CAG重复序列(129)的Q129小鼠表现出强烈的神经学表型，包括共济失调、肌阵挛和癫痫。基于详细的神经病理分析，我们发现尽管有很强的表型，但没有检测到神经元丢失，这表明神经元死亡不是神经退行性变的必要过程。我们进一步发现，突变的DRLA蛋白在核内的积聚是基本的神经病理学发现。此Observ…更多的证据表明，核功能障碍是聚谷氨酰胺疾病的神经变性的基础。基于细胞培养系统，我们证明了使用报告系统严重抑制了CREB依赖的转录激活。我们进一步证明，内源性c-fos转录的激活也被扩展的聚谷氨酰胺伸展段强烈抑制。为了进一步阐明多发性谷氨酰胺病的转录失调机制，我们使用携带全长突变的人DRLA基因的Q76、Q113和Q129作为单拷贝基因进行了详细的表达谱分析，该基因具有不同长度的CAG重复序列(76、113和129重复单位)。我们发现，相当多的基因以时间依赖和重复长度依赖的方式被抑制。在下调的基因中，包括许多cAMP反应基因(c-fos和egr1)，我们已经证明，CREB依赖的转录激活抑制被扩展的聚谷氨酰胺片段强烈抑制，恢复这种抑制是开发治疗聚谷氨酰胺疾病的靶点。较少

项目成果

Yamada, M.: "Involvement of the cerebral cortex and autonomic ganglia in Machado-Joseph disease"Acta Neuropathol. 101. 140-144 (2001)

Yamada, M.：“马查多-约瑟夫病中大脑皮层和自主神经节的参与”《神经病理学报》。

Interference of CREB-dependent transcriptional activation by expanded polyglutamine stretches - Augmentation of transcriptional activation as a potential therapeutic strategy for polyglutamine diseases

扩展多聚谷氨酰胺延伸段干扰 CREB ​​依赖性转录激活 - 增强转录激活作为多聚谷氨酰胺疾病的潜在治疗策略

• 发表时间: 2005
• 期刊: J. Neurochem 93
• 作者: Shimohata;M;Shimohata T;Igarashi;S;Naruse;S;Tsujil;S
• 通讯作者: S

Aprataxin, the causative protein for early-onset ataxia with ocular motor apraxia and hypoalbuminemia, is a nuclear protein wi

Aprataxin 是早发性共济失调伴眼部运动失用症和低白蛋白血症的致病蛋白，是一种核蛋白，具有

• 发表时间: 2004
• 期刊: Ann.Neurol. 55
• 作者: Sano;Y.;Date;H;Igarashi;S;Onodera;O;Oyake;M;Takahashi;T;Hayashi;S;Morimatsu;M;Takahashi;H;Makifuchi;T;Fukuhara;N;Tsuji;S.
• 通讯作者: S.

Yamada, M, Tan, S-H., et al.: "Sharing of polyglutamine transport by the neuronal nucleus and cytoplasm in CAG-repeat diseases"Neuropathol.Appl.Neurobiol.. (in press).

Yamada, M, Tan, S-H. 等人：“CAG 重复疾病中神经元细胞核和细胞质共享多谷氨酰胺转运”Neuropathol.Appl.Neurobiol..（出版中）。

Yamada, M: "Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with dentatorubral-pallidoluysian atrophy."Ann. Neurol.. 49. 14-23 (2001)

Yamada, M：“齿状核红核-苍白球路易体萎缩患者的中枢神经系统神经元中广泛存在核内萎缩蛋白-1 积聚。”Ann。