Molecular and cellular mechanisms of human neurological disease. Cell biological and animal model studies of neurodegeneration, especially in Parkinson's disease, and of primary dystonia,a related functional disease of the motor system.
The central goal of the Dauer laboratory is to unravel the molecular and cellular mechanisms of diseases that disrupt the motor system. Our primary focus is on Parkinson’s disease and DYT1 dystonia. For each of these projects, we focus our efforts on disease genes that cause these disorders, employing a range of molecular, cellular, and whole animal studies to dissect the normal role of disease proteins, and how pathogenic mutations lead to disease. Our Parkinson’s disease- related research is centered upon the biology of leucine-rich repeat kinase 2 (LRRK2), the most common genetic cause of the disease. Using cell biological studies and brain tissue from Parkinson's disease patients, we have found that disease mutations lead LRRK2 to activate the FADD-caspase-8 cell death pathway, and we are currently exploring this pathway in a mouse model of Parkinson's disease. Our dystonia work centers around the biology of torsinA, mutations in which cause the most common genetic form of primary dystonia. We have discovered that neurons have a unique requirement for nuclear envelope-localized torsinA function, and have begun to dissect the mechanisms underlying this neural specificity. These studies involve characterization of a stem cell-based model of torsinA function that mimics the neuronal selective alterations seen in torsinA mutant mice. We have also begun using PET and DTI brain imaging to identify the dysfunctional neural circuit in DYT1 disease mutant "knock in" mice, and we are currently working to dissect the cellular and molecular correlates of these imaging findings.