Molecular Pathogenesis Of Hereditary Spastic Paraplegias

National Institute Of Neurological Disorders And Stroke

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Abstract

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 research theme involves the characterization and functional analysis of the hereditary spastic paraplegia type 3A (SPG3A) protein, atlastin-1. We have recently reported in the journal Cell that atlastin-1 is a member of a ubiquitous family of GTPases that interact with two families of ER shaping proteins to generate the tubular endoplasmic reticulum (ER) network. Interestingly, atlastin-1 interacts with the SPG31 protein REEP1, which is an ER shaping protein, as well as the SPG4 protein spastin, a microtubule-severing ATPase. We have very recently completed a study demonstrating that these three proteins interact with one another to organize the tubular ER network in conjunction with the microtubule cytoskeleton. Since SPG3A, SPG4, and SGP31 account for over 50% of all HSP cases, we suggest ER network defects as the predominant neuropathologic mechanism for the HSPs. In another study, 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 is involved in the degradation of the EGF receptor, prefiguring a critical role for spartin in endocytosis, as well as in cytokinesis through interaction with a novel ESCRT-III protein. 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 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 the progression of these disorders.