Mechanisms of FUS-mediated motor neuron degeneration in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of cortical and spinal motor neurons. Animal models of ALS based on known ALS-causing mutations are instrumental in advancing our understanding of the pathophysiology of motor neuron degeneration. Recent identification of mutations in the genes encoding RNA-binding proteins TDP-43 and FUS has suggested that aberrant RNA processing may underlie common mechanisms of neurodegeneration in ALS and focused attention on the normal activities of TDP-43 and FUS. However, the role of the normal functions of RNA-binding proteins in ALS pathogenesis has not yet been established. In this thesis I present my work on novel FUS-based mouse lines aimed at clarifying the relationships between ALS-causing FUS mutations, normal FUS function and motor neuron degeneration. Experiments in mutant FUS knock-in mice show evidence of both loss- and gain-of-function effects as well as misfolding of mutant FUS protein. Characterization of mice expressing ALS-mutant human FUS cDNA in the nervous system reveals selective, early onset and slowly progressive motor neuron degeneration that is mutation dependent, involves both cell autonomous and non-cell autonomous mechanisms and models key aspects of ALS-FUS. Using a novel conditional FUS knockout mutant mouse, I also demonstrate that postnatal elimination of FUS selectively in motor neurons or more broadly in the nervous system has no effect on long-term motor neuron survival. Collectively, our findings suggest that a novel toxic function of mutant FUS, and not the loss of normal FUS function, is the primary mechanism of motor neuron degeneration in ALS-FUS.