Development and characterization of a new Parkinson's disease model resulting from impaired autophagy.
Development and characterization of a new Parkinson's disease model resulting from impaired autophagy.
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DOI：
10.1523/jneurosci.0209-12.2012
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发表时间：
2012-11-14
期刊：
影响因子：
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通讯作者：
Savitt JM
中科院分区：
文献类型：
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作者：
Ahmed I;Liang Y;Schools S;Dawson VL;Dawson TM;Savitt JM
帕金森病(Parkinson‘s Disease，PD)是一种由遗传因素和环境因素相互作用引起的进行性神经退行性疾病。然而，帕金森病的病因在很大程度上仍不清楚。巨型自噬在异常蛋白质和细胞器的降解中起着至关重要的作用。此外，自噬相关基因(ATG)的缺失会导致神经变性和蛋白质的异常积累。由于这些也是帕金森病的病理特征，自噬的条件性损害可能导致改进的帕金森病动物模型的研究。利用在多巴胺转运体或Engrailed-1启动子控制下表达Cre重组酶的转基因小鼠，我们产生了在黑质致密部、中脑其他区域和后脑的多巴胺神经元中有条件缺失ATG7的小鼠。这种自噬的条件性损害导致与年龄相关的多巴胺能神经元和相应的纹状体多巴胺的丢失，低分子α-突触核蛋白的积聚，以及泛素化蛋白聚集体的存在，概括了帕金森病的许多病理特征。这些有条件的基因敲除动物提供了对帕金森病病理中自噬过程的洞察。
Parkinson’s disease (PD) is a progressive neurodegenerative disease caused by the interaction of genetic and environmental factors. However, the etiology of PD remains largely unknown. Macroautophagy is known to play an essential role in the degradation of abnormal proteins and organelles. Furthermore, the loss of autophagy-related (Atg) genes results in neurodegeneration and abnormal protein accumulation. Since these are also pathologic features of Parkinson disease, the conditional impairment of autophagy may lead to improved animal models for the study of PD. Using transgenic mice expressing Cre recombinase under the control of either the dopamine transporter or the engrailed-1 promoters, we generated mice with the conditional deletion of Atg7 in the dopamine neurons of the substantia nigra pars compacta, other regions of the midbrain, and also the hindbrain. This conditional impairment of autophagy results in the age-related loss of dopaminergic neurons and corresponding loss of striatal dopamine, the accumulation of low molecular weight α-synuclein, and the presence of ubiquitinated protein aggregates, recapitulating many of the pathologic features of PD. These conditional knockout animals provide insight into the process of autophagy in Parkinson disease pathology.