Endocytic Mechanisms in the Hereditary Spastic Paraplegias

细胞神经科的研究集中在一些神经退行性疾病的分子机制上，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。我们最近报道了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。在一项相关研究中，我们研究了被称为肥大综合征(SPG21)的复杂HSP，它是由酸性簇蛋白Maspardin基因的大片段缺失引起的。我们已经产生了Maspardin缺失的小鼠作为这种疾病的小鼠模型，并正在使用行为技术研究这些动物，此外还使用来自这些动物的神经元和其他细胞进行细胞运输研究。2010年，一项关于这一主题的研究发表在《神经遗传学》杂志上。 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。我们正在使用siRNA介导的耗竭研究和结构方法来研究这些蛋白质在细胞中的功能。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。 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 Cellular Neurology Unit 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 recently 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. In a related study, we investigated the complicated HSP known as MAST syndrome (SPG21), which is caused by a large deletion in the gene for the acid cluster protein maspardin. We have generated maspardin-null mice as a murine model for this disorder and are investigating these animals using behavioral techniques in addition to using neurons and other cells derived from these animals for cellular trafficking studies. A study on this topic was published in the journal Neurogenetics in 2010. 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. We are using siRNA-mediated depletion studies and structural approaches to investigate the functions of these proteins in cells. 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. 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.