Endocytic Mechanisms in the Hereditary Spastic Paraplegias

神经遗传学分部细胞生物科的研究重点是一些神经退行性疾病的分子机制，包括线粒体疾病、肌张力障碍和遗传性痉挛截瘫(HSPs)。这些疾病共同困扰着数以百万计的美国人，多年来还在潜移默化地恶化，其中许多人的治疗选择有限。我们的实验室正在研究这些疾病的遗传形式，使用分子和细胞生物学方法来研究疾病基因的突变最终是如何导致细胞功能障碍的。 在过去的几年里，我们研究了SPG11和SPG15这两个最常见的常染色体隐性热休克蛋白突变蛋白之间的相互作用。这些蛋白质相互作用，并与一种新的接头蛋白复合体-AP5相互作用，其中一个成分AP5Z1在SPG48中发生突变。重要的是，我们已经确定了SPG15和SPG11蛋白在溶酶体生物发生和自噬溶酶体重组中的基本作用。这些领域的研究于2014年发表在《临床调查杂志》上。对SPG48蛋白AP5Z1的研究发表在2015年的《人类分子遗传学》和2016年的《神经学：遗传学》上。2018年，我们与李学军博士合作，在《人类分子遗传学》杂志上发表了一项研究，调查了患者诱导的SPG15和SPG48多能干细胞；我们发现轴突内的线粒体结构和功能异常。最后，我们正在研究SPG8蛋白的功能，这是WASH蛋白复合体的一部分，通过改变肌动蛋白细胞骨架参与内体的形成；我们在2016年初在《自然通讯》上发表了一项关于SPG8蛋白的机制研究，另一项研究正在《科学信号》上进行修订。 综上所述，我们希望我们的研究将促进我们对热休克蛋白分子发病机制的理解。在分子和细胞水平上的这种理解将有望导致防止这些疾病进展的新疗法。

Research in the Cell Biology Section, Neurogenetics Branch focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including mitochondrial disorders, dystonia, and the hereditary spastic paraplegias (HSPs). These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for many of them. Our laboratory is investigating inherited forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. Over the past several years, we have studied the interplay of the proteins that are mutated in SPG11 and SPG15, the two most common autosomal recessive HSPs. These proteins interact with one another as well as with a new adaptor protein complex -- AP5, one component of which, AP5Z1, is mutated in SPG48. Importantly, we have identified a fundamental role for the SPG15 and SPG11 proteins in lysosomal biogenesis and autophagic lysosomal reformation. Studies in these areas were published in the Journal of Clinical Investigation in 2014. Studies of the SPG48 protein AP5Z1 were published in Human Molecular Genetics in 2015 and Neurology: Genetics in 2016. In 2018, we published a study in Human Molecular Genetics, in collaboration with Dr. Xue-Jun Li, investigating patient derived induced pluripotent stem cells for SPG15 and SPG48; we found abnormalities in mitochondrial structure and function within axons. Lastly, we are investigating the functions of the SPG8 protein strumpellin, which is part of the WASH protein complex implicated in the shaping of endosomes through alterations of the actin cytoskeleton; we published a mechanistic study of the SPG8 protein in Nature Communications in early 2016 and another study is in revision at Science Signaling. Taken together, we expect that our studies will advance our understanding of the molecular pathogenesis of the HSPs. Such an understanding at the molecular and cellular levels will hopefully lead to novel treatments to prevent the progression of these disorders.