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。 在目前的项目中，我们一直在研究热休克蛋白，这些热休克蛋白是由与内吞转运有关的蛋白质缺陷引起的。其中包括被称为Troyer综合征(SPG20)的复杂HSP，它是由Sartin基因突变引起的，这种突变可能导致Sartin蛋白的完全丧失。我们已经报道了Sartin蛋白与ESCRT-III蛋白IST1相互作用，并参与胞质分裂。我们目前正在通过分析Sartin缺失的小鼠来研究Sartin在神经系统中的功能，这些小鼠是我们作为Troyer综合征的小鼠模型而产生的。对这种小鼠的详细描述发表在2012年的《人类分子遗传学》上。 在过去的一年里，我们已经开始研究SPG11和SPG15中突变的蛋白质之间的相互作用。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。重要的是，我们最近确定了SPG15和SPG11蛋白在溶酶体生物发生和自噬溶酶体重组中的基础作用。这些领域的研究分别于2014年和2015年发表在《临床调查杂志》和《人类分子遗传学》上。最后，我们正在研究SPG8蛋白的功能，它是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。对于所有这些疾病，我们有患者来源的成纤维细胞，我们从这些细胞中创造出诱导的多能干细胞，然后用端脑和多巴胺能神经元来原位模拟这些疾病。 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. In the current project, we have been investigating HSPs that result from defects in proteins implicated in endocytic trafficking. These include the complicated HSP known as Troyer syndrome (SPG20), which is cause by mutations in the spartin gene that likely result in complete loss of the spartin protein. We have reported that the spartin protein interacts with the ESCRT-III protein IST1 and is involved in cytokinesis. We are currently investigating the function of spartin in the nervous system by analyzing spartin-null mice that we have generated as a murine model of Troyer syndrome. A detailed characterization of this mouse was published in Human Molecular Genetics in 2012. Over the past year, we have begun to study the interplay of the proteins that are mutated in SPG11 and SPG15. These proteins interact with one another as well as with a new adaptor protein complex -- AP5. Importantly, we have very recently identifed 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 and in Human Molecular Genetics in 2015. 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. For all of these disorders, we have patient-derived fibroblasts from which we are creating induced pluripotent stem cells, and subsequently telencephalic and dopaminergic neurons to model these disorders in situ. 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.