The goal is to better understand and treat these neurological disorders by using a true bench to bedside approach.
Our group consists of basic science and clinical research components. We use a multi-disciplinary approach to determine the contribution of the basal ganglia and cerebellum to different disorders. We manipulate specific subpopulations of neurons using genetically engineered mice, viral vectors or drug challenges by targeting ion channels, receptors or neurotransmitters to cause or suppress dysfunction. We assess the effects of these manipulations on neuronal function and behavior to pinpoint the source of the dysfunctional signal. Our experiments have resulted in the development and characterization of several mouse models of human disease in our lab and in collaboration with others. This strategy provides a better understanding of the mechanisms underlying neurological dysfunction as well as the development of novel treatments. Our clinical work is aimed primarily at translational research. This includes more precise characterizations of clinical phenotypes, exploring genotype-phenotype relationships, neuroimaging of the brain, biorepositories for exploring biomarkers of disease, and clinical trials of promising new treatments.
Dystonia
Dystonia is characterized by involuntary movements due to excessive or exaggerated muscle activity. The movements depend on the strengths and patterns of muscles involved. In its mildest form, dystonia may appear merely as an exaggeration of an otherwise normal movement. In more serious cases, movements are twisting, stiff, and slow. In its most severe forms, dystonia is characterized by persistent involuntary posturing. Dystonia can occur alone or as a symptom of many other disorders. Although dystonia affects many people, we are just beginning to understand the neurobiological causes.
What brain regions are implicated?
Dystonia traditionally is associated with dysfunction of the basal ganglia, but recent studies have implicated abnormal cerebellar function too. These new studies have led to the concept that dystonia is a motor circuit disorder. Our work focuses on understanding how this circuit gets disrupted.
What neurotransmitters and cell signaling pathways are abnormal?
Some forms of dystonia are linked with dysfunction of dopaminergic pathways, while other studies have revealed dysregulation of cellular calcium homeostasis. Understanding common underlying mechanisms will provide insight into many forms of dystonia.
What can animal models teach us about human dystonia?
Why are females more often affected than males? Why does stress make dystonia worse? What genes contribute to the expression of dystonia? We use mouse models to help us answer these questions, and have an interest in developing monkey models.
Can we identify promising new treatments?
Our anti- dystonia drug discovery program is aimed at identifying new treatments for dystonia, using a screening program based on animal models.
How does dystonia affect people?
We are conducting clinical and translational studies that include documenting natural history and co- morbidities in humans with dystonia, collecting samples for a biorepository for genetic and other biomarker studies, and developing the best designs for clinical trials.
Lesch-Nyhan Disease
Lesch-Nyhan disease (LND) is a human neurogenetic disorder with a characteristic syndrome that includes severe dystonia, mild cognitive disability, and an unusual behavioral profile characterized by an irresistible compulsion to engage in behaviors that are self-injurious. It is caused by mutation of the HPRT1 gene on the X-chromosome. The gene encodes the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), an enzyme that plays a central role in purine biochemistry. Although we know the gene and its product, we do not know the mechanisms that lead to the complex neurobehavioral syndrome. Our group is studying Lesch-Nyhan disease as a model for how defects in a single gene can cause a very complex neurobehavioral phenotype, with a focus on several different questions:
What is the relationship between genotype and phenotype?
Some patients have a much more severe phenotype than others. We have established that this occurs because different mutations cause different defects in the function of the HPRT enzyme, and we want to elucidate how these mutations alter protein function in relation to the severity of the disease. [Refs]
How does HPRT deficiency disrupt developmental programming of dopamine neurons?
We have linked many of the neurobehavioral features with aberrant development of nigrostriatal dopamine neurons. We are interested in using knockout mice and embryonic stem cells in culture to discover how the defect in purine metabolism influences the molecular programs that control dopamine neuron differentiation.
What can Lesch-Nyhan disease tell us about the brain?
This rare disease provides an unusual window for understanding how a complex neurobehavioral phenotype can result from defects in a single-gene, and how one gene can influence dramatically the operations of the normal brain. It also can teach us about other more common diseases.