The Henry L. Paulson Laboratory

Our lab explores the reasons why the aging brain degenerates in neurodegenerative diseases, including Alzheimer’s Disease, Frontotemporal Dementia and polyglutamine expansion disorders such as Huntington disease and Spinocerebellar Ataxia type 3 (SCA3). We pursue 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 and explore how the brain’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, stem cells, organoids 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 and genetic screens to identify compounds and genes that reduce aggregation or lower levels of toxic mutant proteins. We also have pioneered gene silencing approaches, leading to a Phase 1 safety trial of antisense oligonucleotide as therapy for SCA3 patients.

Finally, we are interested in the fundamental role of ubiquitin-dependent protein quality control machinery in neurons. A new line of study investigates Ubiquilins, a class of proteins that link ubiquitin- and chaperone-dependent quality control, accumulate in various degenerative brain diseases, and when mutated directly 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 various diseases.