Research in the Cellular Neurology Unit focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including Parkinson's disease, dystonia, and hereditary spastic paraplegia. 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 year, our laboratory has been concentrating on """"""""disease-related"""""""" members of the dynamin-like family of GTPases -- particularly atlastin-1, OPA1, and Drp1. We have found that the Drp1 GTPase, which is critical for mitochondrial division, interacts with the deafness-dystonia protein DDP. In on-going collaborations with Drs. Richard Youle (NINDS) and Morgan Sheng (HHMI, MIT), we are probing the role of this interaction in mitochondrial division as well as the deafness-dystonia syndrome. Another major project involves the characterization and functional analysis of the hereditary spastic paraplegia type 3A (SPG3A) protein, atlastin-1. We have recently found that although this protein is enriched in the Golgi apparatus, it is also highly enriched in axonal growth cones in neurons. Thus, atlastin-1 may be involved in ER-Golgi membrane dynamics as well as development of axons. Ongoing studies of atlastin-1 are focusing on how subtle changes in structure of the atlastin-1 protein resulting from disease-causing point mutations alter atlastin-1 GTPase activity, Golgi structure and dynamics, atlastin-1 oligomerization, and axonal growth. We have identified several other human atlastin-like proteins (atlastin-2 and -3) and are currently analyzing their localizations and functions. Another dynamin-lke GTPase mutated in an inherited neurological disorder, optic atrophy type 1, is the OPA1 protein. We have recently found that this protein, which is localized to the mitochondria, is critical for maintaining the cristae structure of the mitochondrial inner membrane. Mitochondria are undergoing continual fission and fusion within the cell, and OPA1 is required for proper mitochondrial fusion. The balance between fission and fusion is upset during programmed cell death, and mitochondria undergo extensive fragmentation. Interestingly, we have recently found that the OPA1 protein is released from mitochondria along with cytochrome c during programmed cell death, and we propose that this release may contribute to the increased fragmentation of mitochondria seen during programmed cell death. Lastly, we have recently begun studying the hereditary spastic paraplegia (SPG20; Troyer's syndrome) gene spartin. We have generated antibodies for localization studies, and yeast 2-hybrid screening has identified several interacting proteins, including the endocytic protein Eps15. We anticipate that these studies will allow us to unravel the cellular functions of the SPG20 protein spartin, as well as the effects of patient mutations on these cellular functions. Taken together, we expect that our studies will advance our understanding of the molecular pathogenesis of the hereditary neurological disorders discussed above. 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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