Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms.
Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms.
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DOI：
10.1523/eneuro.0250-16.2017
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发表时间：
2017-03
期刊：
影响因子：
3.4
通讯作者：
Seki K
中科院分区：
文献类型：
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作者：
Tomioka I;Ishibashi H;Minakawa EN;Motohashi HH;Takayama O;Saito Y;Popiel HA;Puentes S;Owari K;Nakatani T;Nogami N;Yamamoto K;Noguchi S;Yonekawa T;Tanaka Y;Fujita N;Suzuki H;Kikuchi H;Aizawa S;Nagano S;Yamada D;Nishino I;Ichinohe N;Wada K;Kohsaka S;Nagai Y;Seki K
与年龄相关的神经退行性疾病，如阿尔茨海默病、帕金森病和多谷氨酰胺（polyQ）疾病，随着人类寿命的延长而变得普遍。虽然已经开发了各种啮齿动物模型来研究和克服这些疾病，但由于与人类在大脑结构和功能以及药物代谢方面的差异，它们在转化研究效用方面存在局限性。在这里，我们建立了多q疾病的转基因狨猴模型，显示进行性神经系统症状，包括运动障碍。通过慢病毒导入人ataxin 3基因，获得了7只具有120个CAG重复序列的转基因狨猴。虽然所有的后代在出生时都没有出现神经系统症状，但转基因表达较高的三只狨猴在出生后3-4个月出现了不同程度的神经系统症状，随后体重增加、自发活动和握力逐渐下降，表明疾病进展依赖于时间。病理检查显示神经退行性变和核内多q蛋白包涵体伴胶质瘤，反映了多q病患者的神经病理特征。与小脑神经元丢失一致，在一只活的有症状的狨猴的脑MRI分析中发现第四脑室增大，这表明小脑萎缩。值得注意的是，在有症状的转基因狨猴配子衍生的第二代后代中证实了成功的种系转基因传播。由于异常蛋白的积累是各种神经退行性疾病的共同病理机制，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病理机制和开发临床适用的治疗方法。
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.