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Instructor Phone: (404) 727-0668 Fax: (404) 727-0570 Email: wrossol@emory.edu Research My main research interest is the biological role of mRNA transport and local translation in neurons and their dysfunction in neurological diseases. Our emphasis is on the axonal function of the spinal muscular atrophy (SMA) disease protein SMN in the development and maintenance of motor neurons. SMA is an inherited neuromuscular disease caused by mutations or deletions in a gene encoding the survival motor neuron protein (SMN) that results in rapid degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMA represents the leading genetic cause of infant mortality. Its pathomechanism is still unclear and currently there is no cure or treatment available to stop its progression. The fundamental question that we seek to understand is why reduction of an essential and ubiquitously expressed protein leads to a very specific pathology in spinal cord motor neurons. We and others have found that in neurons, SMN is located in both the nucleus and in neurites and it is actively transported in the form of dynamic granules. We have also identified a defect in axonal mRNA localization in motor neurons cultured from a transgenic mouse model of Spinal Muscular Atrophy. Taken together, this suggests a novel neuron-specific function of SMN in the transport, stability or local translation of mRNAs. As these processes have been linked to growth cone motility and axon guidance, it is of high interest to find out how SMN may be involved in the delivery of ribonucleoprotein (RNP) complexes. We hypothesize that an inefficiency of axonal SMN-associated RNPs may trigger or at least modulate the disease process in SMA. Our work focuses on animal models of this disease to study the axonal function of SMN. We are particularly interested in identifying and studying axonal transcripts and proteins that are affected by SMN-deficiency. We are also investigating the dynamic localization of SMN containing RNP granules during development, to better understand the biological role of SMN in the development and maintenance of motor axons. In collaboration with the Emory core facilities, we use a variety of approaches. These include proteomics methods, the generation of transgenic mice and the differentiation of stem cells into motor neurons. It is our long-term goal to gain an understanding of the underlying molecular pathology of SMA that will help us to develop novel therapeutic strategies. More broadly, these studies are also important for understanding the function of mRNA localization during the development of the nervous system. |
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