Protein quality control via the disordered E3 ligase San1

Speaker: Associate Professor Richard Gardner, Department of Pharmacology, University of Washington
Host: Professor Rasmus Hartmann-Petersen, Section for Biomolecular Sciences

Dr. Gardner’s research involves the following aspects:

The accumulation of structurally aberrant proteins underlies over 30 human disorders.  These include such devastating diseases as Alzheimer’s, Parkinson’s, Huntington’s, and ALS. Collectively, these disorders are called “protein aggregation” disorders because protein inclusions are usually observed in affected cells. Some protein aggregation diseases result from toxic accumulation in the cytoplasm and extracellular space, but a striking majority (>20) result from toxic accumulation in the nucleus. Of these diseases, there are three main classes: the polyglutamine-expansion class (Huntington’s, Kennedy’s, and several spinal-cereballar ataxias), the polyalanine-expansion class (oculopharyngeal muscular dystrophy and blepharophimosis syndrome), and the random mutant class (neuronal intranuclear inclusion disease and multiple system atrophy). In each case, the process of protein aggregation is thought to be the underlying agent for disease progression. However, it’s not clear how protein aggregation in the nucleus causes toxicity. Specifically, it’s not known what nuclear processes are disrupted to cause cell death. Furthermore, it’s not understood if the different classes of aggregation-prone proteins cause nuclear toxicity in similar or different manners. This aspect of toxicity is important because it will shape how we develop therapeutics to alleviate or prevent these disorders.  To identify the mechanisms of toxicity, we’re using yeast to conduct comprehensive genetic and biochemical analyses of the toxic effects caused by a wide variety of different aggregation-prone nuclear proteins implicated in human disease.  Our hope is to identify cellular processes that can serve as small molecule targets for therapies aimed at these debilitating neurodegenerative diseases.