The Henry L. Paulson Laboratory
The Paulson lab explores the reasons why the aging brain degenerates in neurodegenerative diseases. We primarily study the polyglutamine expansion diseases (including Huntington disease and Spinocerebellar Ataxia type 3), Alzheimer’s Disease, and Frontotemporal Dementia. The lab pursues basic studies of disease mechanisms and translational studies that are leading toward therapies for these fatal diseases.
A common theme in degenerative brain diseases is the tendency for specific proteins to misfold and aggregate. We investigate why these proteins are toxic to neurons and explore how the neuron's protein quality control machinery (chaperones, ubiquitin-proteasome system, autophagy) counteracts this toxicity. To address these questions, we employ techniques ranging from recombinant protein analysis to cell-based assays and engineered mouse models, with corroborating evidence from human disease tissue. Our goal is to understand disease processes so that we can develop therapies for these fatal diseases. Toward that end, we have developed novel cell-based assays and performed drug screens to identify compounds that reduce aggregation or lower levels of toxic mutant proteins. We are now testing identified compounds in mouse models of disease. We also are testing gene silencing approaches as a therapeutic route for such disorders.
Finally, we have developed an interest in the fundamental role of ubiquitin-dependent protein quality control machinery in neurons. For example, we identified a class of ubiquitin ligase subunits that specifically bind sugar residues on glycoproteins and recently discovered an ubiquitin-conjugating enzyme that adds ubiquitin to the amino-termini of proteins rather than to internal lysine residues. A new line of study investigates the Ubiquilin proteins which link ubiquitin- and chaperone-dependent quality control pathways, accumulate in various degenerative brain diseases, and when mutated (in the case of Ubiquilin 2) cause neurodegeneration. We use a variety of biochemical, cellular and gene targeting approaches to determine the role of these and other intriguing ubiquitin-linked proteins in the brain and in various disease states.
Neurodegenerative Diseasesincluding understanding the mechanisms underlying disease and developing potential treatments, specially for diseases with abnormal proteins
Gene silencing strategiesfor use as potential therapy for polyglutamine diseases and dementia
Protein quality controlin normal brain function and in neurodegenerative diseases
Yale University School of MedicineMedical School Training
PhD in Cell Biology