ContactBiomedical Science Tower 3, Room 6063
EducationPhD, Saint Louis University (1999)
We are interested in the function and regulation of monoamine transporters in the brain. The transporter-mediated uptake system is the primary mechanism involved in the termination of monoaminergic signaling, and thus determines the intensity and duration of monoamine transmission at synapses. Despite the importance of biogenic amine transporters in controlling brain function, very little information is available regarding the cellular and molecular regulation of these proteins. This information is essential to understand their contribution to psychiatric disorders and drug addiction. Recently, results from our lab suggest that monoamine transporters are highly regulated proteins and indicate a more complex degree of organization for these transporters than previously anticipated. Findings include the elucidation of the oligomeric nature of DAT, the identification of domains involved in assembly and trafficking, and the identification and characterization of interacting proteins. Based on these results, we hypothesize that monoamine transporters exist as highly regulated macromolecular complexes and that these new regulatory mechanisms might have important implications as novel therapeutic targets.
Neurobiology of the Dystonia-Linked TorsinA Protein: Early-onset torsion dystonia (EOTD) is the most common and severe form of a group of diseases known as dystonias. EOTD is an autosomal dominant movement disorder characterized by involuntary and sustained muscle contractions affecting several parts of the body and resulting in twisting, abnormal postures, and in many cases severe disability. The disease has been recently linked to a three-base pair deletion in the DYT1 gene that results in a single glutamate deletion near the carboxyl terminus of the product of the DYT1 gene, a protein termed torsinA. The mutation causes the protein to aggregate in perinuclear inclusions as opposed to the endoplasmic reticulum localization of the wild-type protein. Although there is increasing evidence that dysfunction of the dopamine system is implicated in the development of EOTD, the biological function of torsinA and its relation to dopaminergic neurotransmission has remained unexplored. We are using biochemical, molecular, and genetic approaches to elucidate the normal biological function of torsinA as well as the relationship between the torsinA mutation and EOTD.
Trainees in the laboratory have the opportunity to participate in a number of research projects related to the function and regulation of monoamine transporters and the neurobiology of torsinA. Specific projects include:1. Monoamine Transporters: The role of oligomerization in transporter function, how transporter proteins are targeted to specific membrane domains, the mechanisms and signals responsible for the regulated trafficking of transporters, the role of interacting proteins in transporter function, and how these mechanisms might be affected by psychostimulants. 2. T
Torres, G.E., Sweeney, A.L., Beaulieu, J.M., Shashidharan, P., and Caron, M.G. Effect of torsinA on membrane proteins reveals a loss of function and a dominant-negative phenotype of the dystonia-associated ?E-torsinA mutant Proc. Natl. Acad. Sci. USA. 101:15650-15655, 2004.