Structural Characterization of Soluble and Neurotoxic Aggregates of FUS (2012 - Present)

Investigator:  Nicolas Fawzi, Brown University
Mentor:  Wolfgang Peti, Brown University

Abstract:  Increasing life expectancy in the United States has been the result of many medical advances.  The occurrence of neurodegenerative diseases associated with older age, however, has therefore also increased.  Although the subject of intense research, effective therapies for these devastating diseases have yet to be found, in large part because the underlying mechanism of toxicity leading to degeneration has yet to be fully understood.  A common link between many of these diseases is the aggregation of proteins into cytotoxic aggregates.  Subtypes of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degenerations (FTLDs) have recently been linked to the formation of cytoplasmic inclusions of RNA binding protein FUS.  Although the toxicity of the aggregates has been investigated in disease models and the connection between the formation of FUS aggregates and disease has been clearly demonstrated, the aggregation process and the mechanisms preventing aggregation under normal conditions have yet to be understood.  Elucidating the molecular details of FUS aggregation using the tools of high-resolution structural biology is the first step in the design of therapies to prevent the formation of toxic aggregates.  Using primarily solution NMR techniques we have developed for the direct observation of aggregating proteins with atomistic resolution, we will test the hypothesis that the N-terminal domain of FUS is unstructured and drives the protein to form toxic aggregates.  We propose three specific aims: 1) Determine the extemt and type of structure in the N-terminal domain of FUS; 2) Determine how the N-terminal domain interacts with the subsequent domains to change aggregation propensity and toxicity; 3) Identify at atomic resolution the residues driving aggregation into FUS aggregates.