PDF(Pubmed)
Abstract：
Mitochondrial dysfunction has been linked to both idiopathic and familial forms of Parkinson\'s disease (PD). We have previously identified RCC1-like (RCC1L) as a protein of the inner mitochondrial membrane important to mitochondrial fusion. Herein, to test whether deficits in RCC1L mitochondrial function might be involved in PD pathology, we have selectively ablated the Rcc1l gene in the dopaminergic (DA) neurons of mice. A PD-like phenotype resulted that includes progressive movement abnormalities, paralleled by progressive degeneration of the nigrostriatal tract. Experimental and control groups were examined at 2, 3-4, and 5-6 months of age. Animals were tested in the open field task to quantify anxiety, exploratory drive, locomotion, and immobility; and in the cylinder test to quantify rearing behavior. Beginning at 3-4 months, both female and male Rcc1l knockout mice show rigid muscles and resting tremor, kyphosis and a growth deficit compared with heterozygous or wild type littermate controls. Rcc1l knockout mice begin showing locomotor impairments at 3-4 months, which progress until 5-6 months of age, at which age the Rcc1l knockout mice die. The progressive motor impairments were associated with progressive and significantly reduced tyrosine hydroxylase immunoreactivity in the substantia nigra pars compacta (SNc), and dramatic loss of nigral DA projections in the striatum. Dystrophic spherical mitochondria are apparent in the soma of SNc neurons in Rcc1l knockout mice as early as 1.5-2.5 months of age and become progressively more pronounced until 5-6 months. Together, the results reveal the RCC1L protein to be essential to in vivo mitochondrial function in DA neurons. Further characterization of this mouse model will determine whether it represents a new model for in vivo study of PD, and the putative role of the human RCC1L gene as a risk factor that might increase PD occurrence and severity in humans.
摘要：
线粒体功能障碍与特发性和家族性帕金森病(PD)有关。我们先前已将RCC1样（RCC1L）鉴定为对线粒体融合重要的线粒体内膜蛋白。在这里，为了测试RCC1L线粒体功能的缺陷是否可能与PD病理有关，我们已经选择性地消融了小鼠多巴胺能(DA)神经元中的Rcc1l基因。导致PD样表型，包括进行性运动异常，伴有黑质纹状体的进行性退化。实验组和对照组在2、3-4和5-6月龄进行检查。在野外任务中测试动物以量化焦虑，探索性驱动，运动，和不动；并在气缸测试中量化饲养行为。从3-4个月开始，雌性和雄性Rcc1l敲除小鼠均表现出僵硬的肌肉和静息性震颤，与杂合或野生型同窝对照相比，后凸畸形和生长缺陷。Rcc1l敲除小鼠在3-4个月时开始显示运动损伤，进展到5-6个月大，Rcc1l敲除小鼠死亡的年龄。进行性运动障碍与黑质致密部（SNc）中酪氨酸羟化酶免疫反应性的进行性和显着降低有关，纹状体中黑色DA投影的急剧损失。早在1.5-2.5个月大的Rcc1l敲除小鼠的SNc神经元中，营养不良的球形线粒体就很明显，直到5-6个月，逐渐变得更加明显。一起,结果表明，RCC1L蛋白对DA神经元的体内线粒体功能至关重要。该小鼠模型的进一步表征将确定它是否代表用于PD体内研究的新模型。以及人类RCC1L基因作为可能增加人类PD发生和严重程度的危险因素的假定作用。
