Endocytic Mechanisms in the Hereditary Spastic Paraplegias

神经遗传学分支细胞生物学部分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性截瘫（HSP）。 这些疾病共同折磨着数百万美国人，在数年内不知不觉地恶化，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如何最终导致细胞功能障碍。 在过去的几年里，我们研究了SPG 11和SPG 15这两种最常见的常染色体隐性热休克蛋白中突变蛋白的相互作用。这些蛋白质相互作用，以及与一个新的衔接蛋白复合物-AP 5，其中一个组成部分，AP 5 Z1，在SPG 48突变。重要的是，我们已经确定了SPG 15和SPG 11蛋白在溶酶体生物发生和自噬溶酶体重组中的基本作用。 这些领域的研究发表在2014年的《临床研究杂志》上。SPG 48蛋白AP 5 Z1的研究发表在2015年的《人类分子遗传学》和2016年的《神经病学：遗传学》上。2018年，我们与Xuo-Jun Li博士合作在Human Molecular Genetics上发表了一项研究，研究了SPG 15和SPG 48的患者来源的诱导多能干细胞;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SPG 8蛋白strumpelin的功能，它是WASH蛋白复合物的一部分，通过改变肌动蛋白细胞骨架参与内体的形成;我们于2016年初在Nature Communications上发表了SPG 8蛋白的机制研究，另一项研究于2020年发表在Science Signaling上。 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新的治疗方法，以防止这些疾病的进展。

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 was published in 2020 in 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.