Johns Hopkins School of Medicine

Disruption of RNA and protein trafficking in neurodegeneration

The Hayes laboratory studies the disruption of RNA and protein trafficking in neurodegeneration with a particular interest in TDP-43, an RNA binding protein disrupted in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and related disorders. Although the causes of ALS and FTD are diverse and only partially understood, a common unifying feature is the nuclear clearance and cytoplasmic aggregation of TDP-43. The upstream cause of TDP-43 mislocalization in disease remains unclear, but abundant evidence suggests that TDP-43 disruption is involved in disease pathogenesis. There is also growing evidence for disruption of other RNA-binding proteins in ALS and FTD, highlighting a critical role for RNA-protein interactions in neuronal biology. We are particularly interested in how nucleocytoplasmic transport and RNA processing intersect to regulate the localization and physiological functions of RNA-binding proteins. Studies in the lab focus on the mechanism and regulation of TDP-43 nucleocytoplasmic transport, the role of RNA in regulating TDP-43 localization and function, and the development of RNA-based approaches to attenuate TDP-43 disruption in disease. To that end, we utilize cellular and molecular techniques in immortalized cell lines and neurons as well as biochemical, biophysical, and computational methods. Our overarching goal is to improve our understanding of the molecular rules governing TDP-43 homeostasis and originate novel therapeutic approaches for neurodegeneration.