The central goal of our studies is to unravel the molecular and cellular mechanisms of diseases that disrupt the motor system. In exploring these diseases, we are also interested in understanding a fundamental question relevant to CNS disease generally: what factors determine the selective vulnerability of particular cell types or circuits to particular insults?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.
Parkinson’s disease is the second commonest age-related neurodegenerative disease after Alzheimer’s disease and is characterized by progressive degeneration of midbrain dopaminergic neurons. Our Parkinson’s disease-related research has focused on mechanisms of degeneration related to abnormalities of alpha-synuclein and leucine-rich repeat kinase 2 (LRRK2), the most common genetic cause of the disease. Our recent work has explored the role of endolysosomal dysfunction in PD-related neurodegeneration, highlighting toxic signals important in cell toxicity that are independent of alpha-synclein dysfunction. In work attempting to understand the reasons for the striking aging-dependence of neurodegenerative disease, we are beginning to explore the role of cell senescence pathways in a novel model of PD neurodegeneration.
Primary dystonia is a neurological disorder characterized by disabling, abnormal, involuntary movements, which can have devastating consequences for the patient. A remarkable aspect of primary dystonia is that mutation in a ubiquitously expressed gene causes a disorder that is highly selective for the developing motor system. We have developed a variety of mouse genetic and in vitro model systems that are enabling us to dissect the molecular and cellular mechanism that explain how a discrete genetic insult disrupts a highly select group of motor structures. This work has led to the discovery of a unique type of neurodegeneration provoked by neurodevelopmental processes (in contrast to the age-related neurodegeneration of PD and related diseases). These studies are based on most common genetic form of primary dystonia, DYT1 dystonia, a dominantly inherited disease caused by a deletion in TOR1A that removes a single glutamic acid (ΔE) from the protein torsinA. TorsinA is AAA+ protein that resides within the endoplasmic reticulum/nuclear envelope endomembrane system, and basic studies of this protein are have also uncovered a novel form of nucleocytosolic transport that appears critical in dystonia pathogenesis.