Deciphering the Mechanisms of RNA-Mediated Toxicity in Neurodegeneration

A common feature across many neurodegenerative disorders is that they are caused by the expansion of nucleotide-repeat sequences in DNA that leads to RNA products that induce cellular toxicity. Despite the central importance of these toxic RNA products in neurodegeneration, we still do not know the mechanism by which these RNAs or their associated hallmarks lead to neurodegeneration. In this proposal, we will make use of our expertise in RNA biology and experience developing innovative new tools for studying RNA biology, RNA-protein interactions, and RNA-mediated bodies in the nucleus to decipher the molecular components of these mutant RNA foci; determine how these RNA-protein aggregates assemble upon disease progression; and understand how they impact global mRNA processing within neurons. Using these approaches, we will explore known repeat-containing RNAs that are genetically linked to neurodegenerative disorders to understand common features of RNA-induced toxicity in neurons.