Cellular and Molecular Mechanisms of FUS-related ALS/FTD

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ALS is a late-onset progressive neurodegenerative disease caused by degeneration of motor neurons, and a disease hallmark is the accumulation of ubiquitin-positive aggregates in neuronal cytoplasm. FUS was identified as genes mutated in both familial and sporadic forms of ALS. In fact, a subset of patients with frontotemporal dementia (FTD) show FUS pathology. FUS, similar to TDP-43, is an RNA binding protein implicated in multiple aspects of RNA metabolism, including splicing, trafficking, and translation. The precise mechanisms of mutated FUS in ALS pathogenesis are not known. To understand the molecular mechanisms of FUS-mediated neurodegeneration, we developed cellular (mammalian primary neuronal and patient-derived iPSC motor neuron) and Drosophila models that recapitulate key features of human disease including cytoplasmic mislocalization, neuromuscular junction defects, locomotor dysfunctions, reduced life span, perturbed stress granule dynamics and toxicity. We discovered muscleblind and drosha as unexpected and novel modifiers of mutant FUS toxicity. MBNL proteins, highly conserved from lower organisms to vertebrates, have been implicated in many neurodegenerative disorders, such as myotonic dystrophy and CAG repeat diseases. The long-term goal is to identify modifiers of FUS toxicity and understand their molecular mechanisms using mammalian cell culture and Drosophila models. The objective of our current application is to determine how muscleblind and drosha modulate FUS-mediated toxicity in Drosophila and FUS iPSC motor neurons. We hypothesize that muscleblind and drosha regulate RNA splicing, SG dynamics and miRNA biogenesis that is perturbed by pathogenic mutations in FUS. We will examine the impact of muscleblind and drosha on cellular and molecular pathologies in FUS-associated neurodegeneration. We expect to dissect the molecular pathways that could be exploited for developing therapeutic interventions for ALS/FTD patients.