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.
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