Stress granules (SGs) are biomolecular condensates that form in response to cellular stress. A plethora of genetic, cell biological and histopathological evidence have implicated SGs in the pathogenesis of neurodegenerative and neuromuscular disorders collectively known as multisystem proteinopathy (MSP), including amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Together, the combined evidence suggests that prolonged stress granule assembly promotes disease, and that mutations in RNA-binding proteins that favor fibrillization can short-circuit this process. Aging of stress granules, including fibrillization from condensates as well as dynamical arrest, have been proposed as mechanisms driving pathogenesis. Hence, SGs are widely viewed as crucibles or birthplaces of neurodegenerative diseases. Other evidence suggest that they could slow down fibril formation of disease relevant proteins such as TDP-43. Here, we will describe our recent work on understanding the driving force for phase separation of proteins, how protein sequences encode material properties and timescales of condensate aging. We will further tackle the mechanism of fibril formation from condensates with implications for our understanding of neurodegenerative diseases.

Dr. Mittag received her PhD from the Johann Wolfgang Goethe University in Frankfurt, Germany, where she used NMR spectroscopy to characterize multistep protein-ligand binding mechanisms. She trained as a Postdoctoral Fellow with Julie Forman-Kay at the Hospital for Sick Children in Toronto, where she revealed how a highly dynamic complex with several interconverting interfaces can encode a cell cycle switch. She joined the Department of Structural Biology at St. Jude Children’s Research Hospital in 2010 and became Full Member in 2021. Her lab uses a spectrum of biophysical, biochemical and cell biological tools to elucidate the mechanism underlying phase separation and its roles in physiological and pathological processes. She was awarded the Michael and Kate Bárány Award for Young Investigators from the Biophysical Society (2021) for her rigorous and foundational contributions to the field of macromolecular condensates and their biological relevance.