Our knowledge of highly defined protein complexes has improved significantly in recent years and we now have an excellent understanding of the molecular organization of complex cellular structures such as the ribosome and the nuclear pore. However, a different kind of molecular assembly, the coalescence of large numbers of proteins and other macromolecules into microscopically visible aggregates, is still largely unexplored despite its significance. Protein aggregates are highly dynamic cellular structures that display tremendous diversity in size, morphology and structural organization. Well known examples of protein aggregates are RNA-containing cytoplasmic bodies such as P bodies and stress granules, which form in an orchestrated physiological response to external and internal stimuli. However, under pathological conditions, aggregation can also result from aberrant interactions between proteins and it is important that we improve our understanding of disease-related aggregation to develop therapeutic interventions for a number of protein misfolding disorders such as Alzheimer's and Parkinson's disease.

Due to the number and complexity of the involved interactions, the mechanisms that govern the assembly of protein aggregates have largely remained elusive. My lab uses an array of cell biological, biochemical and genetic techniques to investigate the molecular mechanisms by which proteins assemble into aggregates. We are also interested in physiological and developmental aspects of protein aggregation, as aggregation serves to compartmentalize and thus regulate diverse cellular functions. We are currently studying a variety of protein aggregates with different structures and diverse functions. One highly-ordered aggregate known as amyloid is at the center of our attention. 

Amyloids form when large numbers of an aggregation-prone protein associate to form a fiber with a single extended β-sheet structure. They initially became known for their association with various neurodegenerative disorders, but more recent studies have shown that they are also generated under a variety of non-pathological conditions and can serve beneficial physiological roles. Amyloids have the ability to replicate their own structure, conferring infectivity on fragments of amyloid that are passed between cells and organisms. One group of proteins with such infectious properties is known as prions. Prions are able to spontaneously convert between structurally and functionally distinct states, at least one of which is a transmissible amyloid. This ability creates a form of molecular memory that has been studied extensively in baker’s yeast. We and others have discovered a number of prions in yeast and we are now studying how they impact diverse biological processes.