Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice
- 作者：Masaki Wakamatsu ; Aiko Ishii ; Shingo Iwata ; Junko Sakagami ; Yuriko Ukai ; Mieko Ono ; Daiji Kanbe ; Shin-ichi Muramatsu ; Kazuto Kobayashi ; Takeshi Iwatsubo ; Makoto Yoshimoto
- 关键词：Parkinson's disease ; Animal model ;
//www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">-Synuclein ; Transgenic mouse ; Tyrosine hydroxylase ; Dopamine neuron
- 刊名：Neurobiology of Aging
- 出版年：2008
- 期刊代码：202_01974580
- 类别：med
- 出版时间：April 2008
- 卷：29
- 期：4
- 页码：574-585
- 文件大小：1954 K
摘要
Parkinson's disease is characterized by loss of nigral dopaminergic neurons and presence of Lewy bodies, whose major component is 
-synuclein. In the present study, we generated transgenic mice termed Syn130m that express truncated human -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 -synuclein did not develop such pathology. Therefore, the truncation of human -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 -synuclein is deleterious to the development and/or survival of nigral dopaminergic neurons.
-synuclein. In the present study, we generated transgenic mice termed Syn130m that express truncated human -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 -synuclein did not develop such pathology. Therefore, the truncation of human -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 -synuclein is deleterious to the development and/or survival of nigral dopaminergic neurons.