Protein quality control mechanisms are the central focus of our research. These mechanisms play a key role in maintaining proteostasis and alleviate proteotoxic stresses. In the secretory pathway, nascent proteins are translocated across the endoplasmic reticulum (ER) membrane. Within the ER, N-glycans are attached, disulfide bonds are formed and proteins acquire secondary and tertiary structure and assemble into oligomeric complexes. Quality control mechanisms monitor folding and assembly, and only proteins that acquire native conformation exit the ER via vesicles and are transported to their final destinations along the secretory pathway.

Our research is aimed to understand the molecular mechanisms that underlie age-related neurodegeneration in general and aggregation of polyglutamine proteins in Huntington’s disease in particular. Relying on the high degree of conservation of the quality control mechanisms and ERAD from yeast to man, our work utilizes molecular cell biology and biochemical techniques, both in cultured mammalian cells and in yeast. The power of yeast genetics and the simplicity of our assays allow identification of age-related pro- or anti-aggregation genes and conditions and the discovery of anti-aggregation drugs. These tools also allow us to study cis-acting signals that confer ER retention and ERAD onto otherwise stable and secreted proteins, as well as cellular trans-acting factors that target these proteins to degradation by the ubiquitin-proteasome system. As a model for cis-acting signals, we investigate elements derived from the immunoglobulin (Ig) molecule  that include CH1, the first constant region in Ig heavy chains, and mstp, the conserved glycosylated C-terminus of the ms heavy chain of secretory IgM. The cellular ERAD components that we focus on, addressing their role in ERAD and their regulation mode, include the AAA-ATPase p97/Cdc48 and the proteasome subunits. Research topics include:

• Yeast as a model system for neurodegenerative disorders
• The p97/Cdc48 AAA-ATPase and its role in ERAD
• ERAD signals