Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice
Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice
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DOI：
10.1016/j.neurobiolaging.2006.11.017
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发表时间：
2008-04
影响因子：
4.2
通讯作者：
Masaki Wakamatsu;A. Ishii;Shingo Iwata;Junko Sakagami;Y. Ukai;Mieko Ono;Daiji Kanbe;S. Muramatsu;Kazuto Kobayashi;T. Iwatsubo;M. Yoshimoto
中科院分区：
文献类型：
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作者：
Masaki Wakamatsu;A. Ishii;Shingo Iwata;Junko Sakagami;Y. Ukai;Mieko Ono;Daiji Kanbe;S. Muramatsu;Kazuto Kobayashi;T. Iwatsubo;M. Yoshimoto
帕金森病的特征是黑质多巴胺能神经元的丧失和路易体的存在，路易体的主要成分是α-突触核蛋白。在本研究中，我们培育了名为 Syn130m 的转基因小鼠，其在多巴胺能神经元中表达截短的人类 α-突触核蛋白（氨基酸残基数：1-130）。值得注意的是，Syn130m 的黑质致密部中的多巴胺能神经元被选择性减少，而表达相当数量的全长人类 α-突触核蛋白的转基因小鼠则没有出现这种病理。因此，人类α-突触核蛋白的截短似乎是黑质多巴胺能神经元损失的主要原因。黑质病理导致纹状体轴突末端损伤，并伴随纹状体多巴胺含量减少。在行为上，Syn130m 的自发运动活动减少，但通过 L-DOPA 治疗可以改善这种异常。黑质多巴胺能神经元的丧失不是进行性的，并且似乎在胚胎发生期间随着转基因表达的开始而发生。我们的结果表明，截短的人 α-突触核蛋白对黑质多巴胺能神经元的发育和/或存活有害。
Parkinson's disease is characterized by loss of nigral dopaminergic neurons and presence of Lewy bodies, whose major component is α-synuclein. In the present study, we generated transgenic mice termed Syn130m that express truncated human α-synuclein (amino acid residue number: 1–130) in dopaminergic neurons. Notably, dopaminergic neurons were selectively diminished in the substantia nigra pars compacta of Syn130m, while transgenic mice that expressed comparable amount of full-length human α-synuclein did not develop such pathology. Therefore, the truncation of human α-synuclein seems to be primarily responsible for the loss of nigral dopaminergic neurons. The nigral pathology resulted in impairment of axon terminals in the striatum and concomitant decrease in striatal dopamine content. Behaviorally, spontaneous locomotor activities of Syn130m were reduced, but the abnormality was ameliorated by treatment with L-DOPA. The loss of nigral dopaminergic neurons was not progressive and seemed to occur during embryogenesis along with the onset of expression of the transgene. Our results indicate that truncated human α-synuclein is deleterious to the development and/or survival of nigral dopaminergic neurons.