Research in the Cellular Neurology Unit focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including Parkinson's disease, dystonia, and 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 hereditary forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. In collaboration with Dr. Mark Cookson's laboratory (NIA), we have found that a point mutation (L166P) of the DJ-1 protein, which causes a form of autosomal recessive Parkinson's disease, causes the protein to be degraded through the proteosome. Thus, Parkinson's disease due to this mutation may essentially be due to the loss of DJ-1 protein. Also, in collaboration with Dr. Morgan Sheng (HHMI/MIT) we have found that the signal transducing adaptor molecule STAM1 interacts with DDP, a mitochondrial intermembrane space protein deleted in the X-linked Mohr-Tranebjaerg deafness-dystonia syndrome; the functional significance of this interaction and any possible involvement in the pathogenesis of the deafness-dystonia syndrome are currently being investigated. Over the past year, our laboratory has been concentrating on """"""""disease-related"""""""" members of the dynamin-like family of GTPases -- particularly Drp1 and atlastin. We have found that the Drp1 GTPase, which is critical for mitochondrial division, interacts with the deafness dystonia protein DDP; we are currently probing the role of this interaction in mitochondrial division and the deafness-dystonia syndrome. We have also identified an intramolecular interaction within the Drp1 protein; mutation of a single amino acid residue critical for this intramolecular interaction markedly reduces GTPase activity of the Drp1 protein. Another major project involves the characterization and functional analysis of the SPG3A protein, atlastin. We have found that atlastin is an oligomeric integral membrane GTPase, most likely tetrameric, localized to the cis-Golgi cisternae within neurons, particularly pyramidal cells of the cerebral cortex. Thus, atlastin may be involved in Golgi membrane dynamics or vesicle trafficking. We are continuing our studies of atlastin, focusing on how subtle changes in structure of the atlastin protein resulting from disease-causing point mutations alter atlastin GTPase activity, Golgi structure and dynamics, and atlastin oligomerization. We have also identified a family of human atlastin-like proteins (atlastin1-3) and are currently analyzing their localizations and functions. 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 four interacting proteins. 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 a the hereditary neurological disorders dicussed above. Such an understanding at the molecular and cellular levels will hopefully lead to novel treatments to prevent progression of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Intramural Research (Z01)
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Hu, Junjie; Shibata, Yoko; Zhu, Peng-Peng et al. (2009) A class of dynamin-like GTPases involved in the generation of the tubular ER network. Cell 138:549-61
Bakowska, Joanna C; Wang, Heng; Xin, Baozhong et al. (2008) Lack of spartin protein in Troyer syndrome: a loss-of-function disease mechanism? Arch Neurol 65:520-4
Rismanchi, Neggy; Soderblom, Cynthia; Stadler, Julia et al. (2008) Atlastin GTPases are required for Golgi apparatus and ER morphogenesis. Hum Mol Genet 17:1591-604
Papapetropoulos, Spiridon; Friedman, Jennifer; Blackstone, Craig et al. (2007) A progressive, fatal dystonia-Parkinsonism syndrome in a patient with primary immunodeficiency receiving chronic IVIG therapy. Mov Disord 22:1664-6
Meijer, Inge A; Dion, Patrick; Laurent, Sandra et al. (2007) Characterization of a novel SPG3A deletion in a French-Canadian family. Ann Neurol 61:599-603
Bakowska, Joanna C; Jupille, Henri; Fatheddin, Parvin et al. (2007) Troyer syndrome protein spartin is mono-ubiquitinated and functions in EGF receptor trafficking. Mol Biol Cell 18:1683-92
Zhu, Peng-Peng; Soderblom, Cynthia; Tao-Cheng, Jung-Hwa et al. (2006) SPG3A protein atlastin-1 is enriched in growth cones and promotes axon elongation during neuronal development. Hum Mol Genet 15:1343-53
Blindauer, Karen; Shoulson, Ira; Oakes, David et al. (2006) A randomized controlled trial of etilevodopa in patients with Parkinson disease who have motor fluctuations. Arch Neurol 63:210-6
Soderblom, Cynthia; Blackstone, Craig (2006) Traffic accidents: Molecular genetic insights into the pathogenesis of the hereditary spastic paraplegias. Pharmacol Ther 109:42-56
Arnoult, Damien; Rismanchi, Neggy; Grodet, Alain et al. (2005) Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol 15:2112-8

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