My lab studies the mechanisms of neurodegenerative diseases with an eye toward developing therapeutics. One major focus is the inherited polyglutamine diseases. Many neurodegenerative disorders are caused by expanded polyglutamine tracts, including Huntington disease and spinocerebellar ataxia type 3 (SCA3). Polyglutamine expansion causes the disease protein to misfold and aggregate in neurons, leading to neuronal death through still uncertain mechanisms. We use various experimental approaches to explore the molecular basis of disease, including cell models and transgenic mice and zebrafish. Major goals are to: 1) determine how neurons ‘handle’ abnormal protein; 2) define the consequences of protein misfolding in neurons; and 3) identify the function of the SCA3 disease protein, which is closely linked to ubiquitin-mediated pathways. Neurodegenerative disease proteins are often toxic to neurons. Accordingly, we are now using the powerful tool of RNA interference to suppress the expression of various neurodegenerative disease genes, including polyglutamine disease genes, dystonia genes and Alzheimer disease genes. Using animal models, we are determining whether this potential therapeutic strategy holds promise in humans. In a third set of studies, we are investigating the complex neuronal machinery that regulates protein ubiquitination and degradation. In neurons, the ubiquitin-proteasome pathway is important not only for the elimination of ‘toxic’ proteins but also for the regulated destruction of normal proteins. We have identified a novel family of ubiquitin ligases that regulate glycoprotein homeostasis. Molecular, cellular and animal knockout approaches are being used to address the role of these ubiquitin ligases in the brain and elsewhere. Lab web site: http://www.medicine.uiowa.edu/paulson/