Stress granules the focus of molecular, cellular basis of neurodegenerative diseases
Rohit Pappu, Tanja Mittag at St. Jude to continue foundational work on basis of Alzheimer’s disease, ALS, frontotemporal dementia
Amyotrophic lateral sclerosis (ALS) generally begins with muscle weakness and progresses over time. While an exact cause in most patients with the disease is unknown, researchers know that nerve cells are under attack.
Rohit Pappu, the Gene K. Beare Distinguished Professor in the McKelvey School of Engineering at Washington University in St. Louis, and collaborator Tanja Mittag, of the St. Jude Children’s Research Hospital Department of Structural Biology, are investigating stress granules that are implicated in the beginnings of neurodegenerative diseases such as ALS, frontotemporal dementia and Alzheimer’s disease. Already making progress in their research, they have been awarded an additional $3.4 million from the National Institutes of Health’s National Institute of Neurological Disorders and Stroke to continue their work for an additional five years. Their initial work began in 2021.
Stress granules form in response to cellular stresses and are designed to protect cells from the harmful consequences of stress, which include the release of untranslated naked unfolded messenger RNA (nuRNAs) into cells. Stress granules form via reversible co-phase separation of G3BP, a family of multifunctional RNA-binding proteins, and nuRNA molecules. They also recruit RNA-binding proteins with RNA-recognition motifs and prion-like low complexity domains from the fluid inside a cell and the nucleus.
“A key unanswered question is how RNA-binding proteins contribute to the capacity of stress granules to buffer against nuRNAs,” said Pappu, a professor of biomedical engineering. “Answering this question is central to enhancing the buffering capacity of stress granules, which will likely be a productive way to intervene therapeutically in Alzheimer’s disease, ALS and frontotemporal dementia.”
The research teams at WashU and St. Jude will test the hypothesis that certain proteins help stress granules and similar cell clusters form more easily by handling RNA.
“Paradoxically, by using RNA-binding proteins to assemble stress granules, cells seem to create an inherent risk for themselves,” Pappu said. “We recently found that the threshold concentration for amyloid fibril formation of an archetypal stress granule-associated RNA-binding protein is lower than the threshold RNA-binding protein concentration for condensation that drives stress granule assembly.”
Mutations that cause disease further increase the condensation threshold of RNA-binding proteins, while lowering their threshold concentration for fibril formation. This gap between threshold concentrations creates a toxic scenario whereby amyloid formation of RNA-binding proteins can become an inevitable thermodynamic consequence of SG assembly.
“Our second crucial and as yet unanswered question is how cells form functional stress granules while avoiding fibril formation of their RBPs,” Pappu said.
The team aims to answer this question through biophysical and biochemical approaches that combine computations based on machine learning, theory and experiments. If their hypothesis is valid, their findings will represent a paradigm shift in the thinking about the roles of stress granules in pathology and will be foundational and important to determine strategies toward therapeutic treatments of currently untreatable neurodegenerative diseases.
