Research in the Cellular Neurology Unit focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including Parkinson's disease, dystonia, optic atrophy, and spastic paraplegia. These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for most. 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. We have recently been concentrating on """"""""disease-related"""""""" members of the dynamin-like family of GTPases -- particularly OPA1, atlastin, Drp1, and MxA. Two of these, atlastin and OPA1, are mutated in hereditary spastic paraplegia type 3A (HSP3A) and optic atrophy type 1, respectively. MxA is a protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. The dynamin-like GTPases are thought to function in the division of a variety organelles (e.g., mitochondria), or by otherwise modifying organellar morphology within cells. We have recently found that the Drp1 GTPase, which is critical for mitochondrial division, interacts with DDP/TIMM8a, a mitochondrial intermembrane space protein deleted in the X-linked Mohr-Tranebjaerg deafness-dystonia syndrome; we are currently probing the role of this interaction in mitochondrial division and the deafness-dystonia syndrome. Another project involves the characterization and functional analysis of the HSP3A protein, atlastin. We have found that atlastin is an oligomeric protein, most likely tetrameric, which can form still higher order oligomers under certain conditions. When overexpressed in cell lines, atlastin localizes to the membrane of the endoplasmic reticulum (ER). Interestingly, expression of atlastin with the point mutations found in HSP3A patients results in abnormalities in ER structure. Thus, atlastin may be involved in regulating ER morphology. We are continuing our studies of atlastin, focusing on how subtle changes in structure of the atlastin protein alter function, and also how this altered function results in cell death. Ultimately, understanding how mutations in atlastin and other members of the dynamin-like GTPase family cause cell death may provide insight into new ways to prevent the progression of several neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Intramural Research (Z01)
Project #
1Z01NS002992-01
Application #
6671484
Study Section
(CNU)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2002
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
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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