Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute 'C. Besta', Milan, Italy.
Hum Mol Genet. 2012 Dec 15;21(24):5294-305. doi: 10.1093/hmg/dds380. Epub 2012 Sep 13.
Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration.
神经退行性伴脑铁沉积症（NBIA）是一组以脑铁含量高和轴突球体存在为特征的神经退行性疾病。编码泛酸激酶 2 的 PANK2 基因突变导致辅酶 A 代谢的常染色体隐性先天性错误，称为泛酸激酶相关神经变性（PKAN）。PKAN 的特征是肌张力障碍、构音障碍、僵硬和色素性视网膜变性。这种疾病的发病机制尚不清楚，尽管 PANK2 是一种线粒体蛋白，但尚未报道线粒体生物能学的紊乱。PKAN 的敲除（KO）小鼠模型表现出视网膜变性和无精子症，但缺乏任何神经表型。由于人类和鼠类 PANK2 蛋白的细胞定位不同，部分解释了缺乏临床表型的原因。在这里，我们证明了鼠类 Pank2 蛋白定位于线粒体，类似于其人类同源物。此外，我们还表明，来自 KO 小鼠的 Pank2 缺陷神经元具有改变的线粒体膜电位，这一缺陷进一步通过超微结构水平观察到的线粒体肿胀和呼吸缺陷得到证实。
