MPI-NAT Symposium: Molecular mechanisms of RNA-binding protein dysfunction in neurodegenerative disorders

The talk will focus on molecular mechanisms that underlie the dysfunction of intrinsically disordered RNA-binding proteins (RBPs) in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer’s disease. Of particular interest are the RBPs TDP-43 and FUS, which are genetically linked to ALS and form aberrant cytoplasmic aggregates in the degenerating brain regions of patients. Our previous work has shown that RBP mislocalization and aggregation is driven by defects in nuclear import and aberrant phase separation and that both events are heavily regulated by post-translational modifications. I will provide insights into how we recently discovered important control mechanisms of RBP phase transitions, such as nuclear import receptors and post-translational modifications. I will discuss how we are currently addressing the link between RBP phase separation and aggregation, using TDP-43 as a paradigm. Finally, I will show our ongoing research efforts to address the physiological relevance of RBP phase separation, e.g. for RNA processing and DNA damage repair, and outline future research perspectives.