Mechanism of FUS Mutations in the Pathogenesis of ALS

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DESCRIPTION (provided by applicant): ALS is a fatal disease caused by the selective degeneration of motor neurons in the central nervous system. Patients with ALS suffer from severe muscle wasting/weakness and eventually die from respiratory failure. Recent genetic data have shown that mutations in the FUS gene can be identified in more than 5% of patients with familial and sporadic ALS. The identification of additional genetic causes, such as FUS mutations, strongly indicate the urgent needs to develop new model systems to understand these mutations and to identify therapeutic targets for these devastating diseases. One important pathological feature in ALS patients with FUS mutations is the presence of abnormal protein aggregates in motor neurons prior to their degeneration. However, it is unclear if abnormal protein aggregates directly contribute to the degeneration of the motor neurons. Based on the function of FUS as a RNA binding protein, we hypothesize that mutation in FUS interferes with normal RNA/protein synthesis, which ultimately leads to cell death and the degeneration of motor neuron synapses. To further investigate the mechanisms of FUS mutations, we propose to establish cellular and mouse models to characterize the effects of FUS mutant proteins in RNA transport and synthesis. Our goal is to establish both cellular and transgenic mouse models to determine how mutant FUS proteins lead to neuronal cell death and the maintenance of the neuromuscular junction. In support of this view, our data indicate that spinal motor neurons in transgenic mice expressing mutant FUS proteins show severe disruption in RNA and protein synthesis machinery. These exciting results give us the confidence that our proposed experiments are highly achievable within the two years funding period of the Therapeutic Idea Award. They further provide strong supports that these models will serve as novel platforms for the development of high throughput drug screening to identify therapeutic targets that can block cell death in motor neurons and restore innervation at the neuromuscular junction.