Jang Minhee, Lee Seung Eun, Cho Ik-Hyun
Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
Virus Facility, Research Animal Resource Center, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
Front Cell Neurosci. 2018 Jun 12;12:157. doi: 10.3389/fncel.2018.00157. eCollection 2018.
Huntington's disease (HD) is an autosomal-dominant inherited neurodegenerative disorder characterized by motor, psychiatric and cognitive symptoms. HD is caused by an expansion of CAG repeats in the huntingtin () gene in various areas of the brain including striatum. There are few suitable animal models to study the pathogenesis of HD and validate therapeutic strategies. Recombinant adeno-associated viral (AAV) vectors successfully transfer foreign genes to the brain of adult mammalians. In this article, we report a novel mouse model of HD generated by bilateral intrastriatal injection of AAV vector serotype DJ (AAV-DJ) containing N171-82Q mutant (82Q) and N171-18Q wild type (18Q; sham). The AAV-DJ-82Q model displayed motor dysfunctions in pole and rotarod tests beginning 4 weeks after viral infection in juvenile mice (8 weeks after birth). They showed behaviors reflecting neurodegeneration. They also showed increased apoptosis, robust glial activation and upregulated representative inflammatory cytokines (tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6), mediators (cyclooxygenase-2 and inducible nitric oxide synthase) and signaling pathways (nuclear factor kappa B and signal transducer and activator of transcription 3 (STAT3)) in the striatum at 10 weeks after viral infection (14 weeks after birth) via successful transfection of mutant into neurons, microglia, and astrocytes in the striatum. However, little evidence of any of these events was found in mice infected with the AAV-DJ-18Q expressing construct. Intrastriatal injection of AAV-DJ-82Q might be useful as a novel model to investigate the biology of truncated N-terminal fragment (N171) in the striatum and to explore the efficacy of therapeutic strategies for HD.
亨廷顿舞蹈症（HD）是一种常染色体显性遗传的神经退行性疾病，其特征为运动、精神和认知症状。HD是由亨廷顿蛋白（）基因中的CAG重复序列在包括纹状体在内的大脑各个区域发生扩增所致。目前用于研究HD发病机制和验证治疗策略的合适动物模型较少。重组腺相关病毒（AAV）载体可成功将外源基因导入成年哺乳动物的大脑。在本文中，我们报告了一种新型HD小鼠模型，该模型通过双侧纹状体内注射携带N171 - 82Q突变型（82Q）和N171 - 18Q野生型（18Q；假手术组）的AAV血清型DJ（AAV - DJ）载体构建而成。AAV - DJ - 82Q模型在幼年小鼠（出生后8周）病毒感染4周后，在转棒试验和杆试验中表现出运动功能障碍。它们呈现出反映神经退行性变的行为。在病毒感染10周后（出生后14周），通过将突变型成功转染到纹状体中的神经元、小胶质细胞和星形胶质细胞中，它们还表现出纹状体内凋亡增加、强烈的胶质细胞激活以及代表性炎症细胞因子（肿瘤坏死因子 - α（TNF - α）和白细胞介素（IL） - 6）、介质（环氧化酶 - 2和诱导型一氧化氮合酶）和信号通路（核因子κB和信号转导及转录激活因子3（STAT3））上调。然而，在感染表达构建体AAV - DJ - 18Q的小鼠中未发现上述任何事件的明显证据。纹状体内注射AAV - DJ - 82Q可能作为一种新型模型，用于研究纹状体中截短的N端片段（N171）的生物学特性，并探索HD治疗策略的疗效。
