Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice
Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice
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DOI：
10.1074/jbc.m413955200
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发表时间：
2005-06-03
影响因子：
4.8
通讯作者：
Zhuang, XX
中科院分区：
文献类型：
--
作者：
Chen, LN;Cagniard, B;Zhuang, XX
DJ-1基因突变最近在一种常染色体隐性遗传形式的早发性家族性帕金森病中被发现。结构生物学、生物化学和细胞生物学研究表明，DJ-1在氧化应激、蛋白质折叠和降解途径中具有潜在的功能。然而，需要动物模型来确定DJ-1功能丧失是否以及如何导致帕金森病。我们已经产生了DJ-1缺失小鼠，其突变与患者报告的大片段缺失突变相似。我们的行为分析表明，DJ-1缺乏导致年龄依赖和任务依赖的运动行为缺陷，这些缺陷在5个月大的时候就可以检测到。无偏见的体视学研究没有发现6个月和11个月大的小鼠明显的多巴胺神经元丢失。神经化学检查显示纹状体多巴胺能功能发生显着变化，包括多巴胺重摄取率增加和组织多巴胺含量增加。这些数据代表了体内证据，即DJ-1功能的丧失会改变黑质纹状体的多巴胺能功能，并产生运动障碍。
Mutations in the DJ-1 gene were recently identified in an autosomal recessive form of early-onset familial Parkinson disease. Structural biology, biochemistry, and cell biology studies have suggested potential functions of DJ-1 in oxidative stress, protein folding, and degradation pathways. However, animal models are needed to determine whether and how loss of DJ-1 function leads to Parkinson disease. We have generated DJ-1 null mice with a mutation that resembles the large deletion mutation reported in patients. Our behavioral analyses indicated that DJ-1 deficiency led to age-dependent and task-dependent motoric behavioral deficits that are detectable by 5 months of age. Unbiased stereological studies did not find obvious dopamine neuron loss in 6-month-and 11-month-old mice. Neurochemical examination revealed significant changes in striatal dopaminergic function consisting of increased dopamine reuptake rates and elevated tissue dopamine content. These data represent the in vivo evidence that loss of DJ-1 function alters nigrostriatal dopaminergic function and produces motor deficits.