People

Many human movement disorders are caused by protein misfolding and aggregation in neurons and glia.  Parkinson's disease and multiple system atrophy are characterized by accumulation of misfolded alpha-synuclein, whereas misfolded MAP-tau accumulates in progressive supranuclear palsy and corticobasal degeneration.  In addition, primary torsion dystonia is caused by loss of function of torsin, an endoplasmic reticulum chaperone.  We have generated novel zebrafish models allowing us to study the pathogenesis of these diseases and to isolate chemical modifiers as a first step towards drug discovery.  We also have a research program evaluating gene therapy approaches in these diseases.

My laboratory studies organelle homeostasis, compartmentalized signals and cellular quality control in genetic and toxin models of neurodegeneration. In particular, we are interested in the mitochondrial lifecycle, and the role of proteins mutated in Parkinson’s disease, dementia and hereditary mitochondrial diseases in regulating neuron morphology and health. Using cell biologic, molecular imaging and mass spectrometry approaches, my team studies post-translational modifications and transcriptional (mtDNA and nDNA) mechanisms that mediate catabolic-anabolic imbalances in neurodegeneration.

Our laboratory studies the pathobiology underlying neurodegenerative diseases. We are interested in the discovery of pathways whose dysfunction contributes to neuronal death observed in a motor neuron disease, Amyotrophic Lateral Sclerosis (ALS), and dementias such as Frontotemporal Dementia (FTD). A hallmark neuropathological feature of neurodegenerative diseases is intracellular protein inclusions. We employ novel approaches to assess both the molecular triggers that initiate inclusion formation and identify modifiers of these pathological inclusions. Commonly used strategies in our laboratory include the generation of induced pluripotent stem cell neurons from ALS/FTD patient fibroblasts, optogenetic induction of neurodegenerative proteinopathies, and light-induced assembly of functional membraneless ogranelles.

Our laboratory combines NMR spectroscopy with Biophysics, Biochemistry, and Chemistry to investigate cellular processes at the molecular and atomic levels in relation to human disease. We presently focus on three main areas in biology: HIV pathogenesis, structural methods, such as NMR spectroscopy and X-ray crystallography, protein-carbohydrate recognition, and protein deposition diseases. In order to understand how biological macromolecules work and intervene in a rational manner with respect to activity and function, detailed knowledge of their architecture and dynamic features is required. Evaluation of the major determinants for stability and conformational specificity of normal and disease-causing forms of these molecules, will allow us to unravel the complex processes associated with disease.

The Kleyman laboratory focuses on studies of Na and K  channels that are found in epithelia. How are epithelial Na channels regulated by extracellular factors, including Na, shear stress, and proteases? What are the roles of epithelial Na channels in non-epithelial tissues? What are the roles on WNK kinases in facilitating adaptive changes in K channel expression in response to increased dietary K intake?

The major research foci of the Leak lab include 1) the transmission of proteinopathic stress across neuroanatomical circuitry in Parkinson’s disease and 2) adaptive responses to subtoxic proteinopathic and oxidative stress—a phenomenon known as preconditioning or tolerance. Recent studies in Dr. Leak’s lab have established that α-synucleinopathy can be transmitted from superficial olfactory structures deep into the brain in vivo, consistent with the olfactory vector hypothesis of Parkinson’s disease, and have provided evidence for robust cross-hemispheric preconditioning of the nigrostriatal pathway in an animal model of Parkinson’s disease.

Research in the O’Donnell lab focuses on the molecular mechanism underlying selective protein trafficking. Specifically, we use studies of alpha-arrestins, a recently identified class of trafficking adaptor, to define key events in molecular selection and post-translational regulation of protein trafficking, as well as to define previously uncharacterized protein trafficking pathways. Our work uses the budding yeast Saccharomyces cerevisiae as a model system and we are currently applying insights from yeast to guide directed studies in mammalian cells. 

Research in the Sorkin laboratory is currently split into two major directions which are apparently distinct from each other with respect to the cell type, relation to the human disease, and experimental models used. However, the main idea underlying both directions is conceptually the same - to understand how trafficking regulates function(s) of transmembrane proteins, such as receptors and transporters. One major project aims at elucidating the molecular mechanisms of endocytosis of growth factor receptors and analyzing the role of endocytosis in regulation of signal transduction by these receptors using a prototypic member of the family, epidermal growth factor (EGF) receptor as the main experimental system. Another major research direction is the study of the role of trafficking processes in the regulation of the plasma membrane dopamine transporter in central nervous system. In both of these research areas we are using a multidisciplinary approach, and a combination of in vitro and in vivo experimental models.

The focus of the research in the Thathiah lab is to study the cellular and molecular mechanisms involved in the pathogenesis of Alzheimer´s disease (AD). Neuropathologically, the brains of AD patients are characterized by the accumulation of aggregates of the amyloid-β (Aβ) peptide and neurofibrillary tangles, which are composed of the hyperphosphorylated microtubule-associated protein tau. The Thathiah lab investigates the involvement of G protein-coupled receptors (GPCRs) in modulation Aβ and tau pathology and the cross-talk between Aβ and tau in disease progression. We combine cellular and biochemical techniques with mouse models of neurodegeneration and behavioral studies to address our research questions.

Our research interests include the total synthesis of natural products, organometallic, heterocyclic, medicinal and computational chemistry. We study chemical reactivity, develop synthetic methods to augment the chemical toolbox, and collaborate to develop new therapeutics.