Developing in vivo and in vitro Models for ALS Caused by Mutant FUS

Thomas Jefferson University, Philadelphia PA

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Abstract

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS), a common neurodegenerative disease, is characterized by progressive degeneration of motor neurons and denervation atrophy of skeletal muscles. ALS inexorably progresses to paralysis and death. At present, ALS is incurable. Most ALS cases are sporadic, with about 20% having family history. A recent advance in ALS research is the discovery of pathogenic mutations in the Fused in Sarcoma (FUS) gene in ALS. FUS is a highly conserved ribonucleoprotein encoded by the FUS gene of 15 exons. While the physiological functions of FUS are largely unknown, mutation in FUS is definitely linked to ALS. Up to date, no in vivo data on FUS mutation has been available. A critical step in dissecting a disease gene is establishing reproducible models that express the disease gene with pathogenic mutations and develops disease phenotypes observed in patients. While cultured cells and invertebrate animals are the most useful models for studying molecular interactions, modeling mutant FUS-linked ALS must involve an intact system such as rodents that can replicate the complex phenotypes of the central nervous system. Therefore, we will create transgenic rats expressing the normal or the mutant human FUS gene. We choose rats rather than mice to express the disease gene because rats are the preferred animals for pharmacologic studies. Our ultimate goal is to find a cure for ALS. In proposed studies, we will thoroughly characterize transgenic rats expressing pathogenically mutated FUS. We will also develop a physiologically relevant cell model for the FUS mutation by deriving neuron- restricted progenitor cells from FUS transgenic rats. As two complementary model systems, FUS transgenic rats and primary neuronal cells would be useful to mechanistic studies of the ALS and could be suitable for testing potential therapies for ALS. PUBLIC HEALTH RELEVANCE: This proposal will develop a FUS transgenic rat model for amyotrophic lateral sclerosis caused by mutation in the FUS gene. The resulting rat model would be useful to mechanistic study of the disease and could be suitable for testing potential therapies for this devastating disease, having a direct impact on patient health.