Departamento de Bioquimica e Imunologia, ICB, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
Mol Neurobiol. 2011 Feb;43(1):1-11. doi: 10.1007/s12035-010-8153-1. Epub 2010 Dec 9.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary body movement, cognitive impairment and psychiatric disturbance. A polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein is the genetic cause of HD. Htt protein interacts with a wide variety of proteins, and htt mutation causes cell signaling alterations in various neurotransmitter systems, including dopaminergic, glutamatergic, and cannabinoid systems, as well as trophic factor systems. This review will overview recent findings concerning htt-promoted alterations in cell signaling that involve different neurotransmitters and trophic factor systems, especially involving mGluR1/5, as glutamate plays a crucial role in neuronal cell death. The neuronal cell death that takes place in the striatum and cortex of HD patients is the most important factor underlying HD progression. Metabotropic glutamate receptors (mGluR1 and mGluR5) have a very controversial role in neuronal cell death and it is not clear whether mGluR1/5 activation either protects or exacerbates neuronal death. Thus, understanding how mutant htt protein affects glutamatergic receptor signaling will be essential to further establish a role for glutamate receptors in HD and develop therapeutic strategies to treat HD.
亨廷顿病（HD）是一种常染色体显性神经退行性疾病，其特征是不自主的身体运动、认知障碍和精神障碍。亨廷顿蛋白（htt）氨基末端区域的多聚谷氨酰胺扩展是 HD 的遗传原因。htt 蛋白与多种蛋白质相互作用，htt 突变导致各种神经递质系统（包括多巴胺能、谷氨酸能和大麻素系统以及营养因子系统）中的细胞信号改变。本综述将概述最近关于 htt 促进涉及不同神经递质和营养因子系统的细胞信号改变的发现，特别是涉及 mGluR1/5 的发现，因为谷氨酸在神经元细胞死亡中起着至关重要的作用。HD 患者纹状体和皮质中发生的神经元细胞死亡是 HD 进展的最重要因素。代谢型谷氨酸受体（mGluR1 和 mGluR5）在神经元细胞死亡中具有非常有争议的作用，并且不清楚 mGluR1/5 的激活是保护还是加剧神经元死亡。因此，了解突变 htt 蛋白如何影响谷氨酸能受体信号对于进一步确定谷氨酸受体在 HD 中的作用以及开发治疗 HD 的治疗策略至关重要。
