Department of Neurophysiology, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
Department of Degenerative Neurological Diseases, National Institute of Neuroscience National Center of Neurology and Psychiatry , Tokyo 187-8502, Japan.
eNeuro. 2017 Mar 28;4(2). doi: 10.1523/ENEURO.0250-16.2017. eCollection 2017 Mar-Apr.
Age-associated neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3-4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.
与年龄相关的神经退行性疾病，如阿尔茨海默病、帕金森病和多聚谷氨酰胺（polyQ）疾病，随着人类寿命的延长而变得越来越普遍。尽管已经开发了各种啮齿动物模型来研究和克服这些疾病，但由于大脑结构和功能以及药物代谢方面与人类存在差异，它们在转化研究中的应用存在局限性。在这里，我们生成了一种多聚 Q 疾病的转基因狨猴模型，该模型表现出进行性神经症状，包括运动障碍。通过慢病毒引入携带编码扩展多聚 Q 延伸的 120 个 CAG 重复的人类 Ataxin 3 基因，产生了 7 只转基因狨猴。尽管所有后代出生时均无神经症状，但在出生后 3-4 个月，3 只转基因表达较高的狨猴出现了不同程度的神经症状，随后体重增加、自发活动和握力逐渐下降，表明疾病呈进行性发展。病理检查显示神经退行性变和核内 polyQ 蛋白包涵体伴有神经胶质增生，再现了 polyQ 疾病患者的神经病理学特征。与小脑神经元丢失一致，对一只有症状的活体转基因狨猴的脑 MRI 分析检测到第四脑室扩大，提示小脑萎缩。值得注意的是，从有症状的转基因狨猴配子中衍生的第二代后代中成功地进行了种系转基因传递。由于异常蛋白的积累是各种神经退行性疾病的共同发病机制，我们认为这种新的狨猴模型将有助于阐明神经退行性疾病的发病机制，并开发出临床上可应用的治疗方法。
