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 this project, we are focusing on the HSPs. One major theme involves the characterization and functional analysis of the hereditary spastic paraplegia type 3A (SPG3A) protein, atlastin-1. We have reported that although this large GTPase is enriched in vesicular tubular complexes and cis-Golgi apparatus in cells, it is also highly enriched in axonal growth cones in neurons. We found that some SPG3A patient mutations result in decreased GTPase activity of the atlastin-1 protein, while others appear to decrease protein stability. Modeling these loss-of-function changes in cultured neurons using shRNA, we found that loss of atlastin-1 inhibits the growth of axons, presenting a compelling case for abnormal development in the pathogenesis of the very early onset hereditary spastic paraplegia type 3A. More recently, we have been studying several other human atlastin-like proteins (atlastin-2 and -3) that we identified. We have determined that, in contrast to atlastin-1, these two proteins localize to the endoplasmic reticulum. However, all atlastins appear to be important for ER and Golgi morphogenesis. We are currently identifying atlastin-interacting proteins by co-precipitation studies and yeast two-hybrid screening to clarify further their functional roles within cells. ? ? In another project, we have been studying the complicated HSP known as Troyer syndrome (SPG20), which is cause by a mutation in the spartin protein. Interestingly, we have found that the spartin protein, like its interaction partner Eps15, is involved in the internalization and degradation of the EGF receptor, prefiguring a critical role for spartin in endocytosis. 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 addition, we very recently reported the clinical features of a new Old Order Amish family with Troyer syndrome and showed that the spartin protein is completely absent in cells derived from these patients. ? ? In a final project related to the HSPs, we have been investigating the complicated HSP known as MAST syndrome (SPG21), which is caused by a large deletion in 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 form these animals for cellular trafficking studies. Lastly, we have recently completed a study characterizing the interaction of the maspardin protein with a specific isoform of aldehyde dehydrogenase, ALDH16A1. ? ? 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 progression of these disorders.
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