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• W2769364032 abstract "Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease, and is characterized by the loss of both upper and lower motor neurons. Recently, mutations in genes that encode for RNA-binding proteins have been linked to ALS pathology, suggesting that perturbation of RNA processing may be affiliated with disease pathogenesis. Mutations of the gene Fused in Sarcoma (FUS), which codes for the protein FUS, have been linked to both familial and sporadic forms of ALS. FUS is a DNA/RNA-binding protein that plays critical roles in RNA processing including RNA trafficking and alternative splicing. Using a Drosophila melanogaster model for FUS-associated ALS that was developed by our laboratory, we performed an unbiased genetic screen to identify dominant modifiers of ALS-associated neurodegeneration. Unexpectedly, we identified muscleblind (mbl), the Drosophila homolog of human muscleblind-like (MBNL) as a strong suppressor of FUS-mediated neurodegeneration in vivo. We found that RNAi-mediated knockdown of endogenous Drosophila mbl rescues neurodegenerative phenotypes such as retinal degeneration, reduced life span and neuromuscular junction defects caused by ALS-associated mutations in FUS. We validated our findings in a mammalian primary cortical neuron system and found that depleting endogenous muscleblind-like strongly suppressed dendritic morphological defects and toxicity. Interestingly, we found in both human embryonic kidney cells and primary cortical neurons that muscleblind protects against FUS toxicity by reducing pathogenic incorporation of mutant FUS into cytoplasmic stress granules. Taken together, our data suggests an unexpected role of mbl in FUS-mediated neurodegeneration and demonstrates that muscleblind is a regulator of toxicity associated with mutant FUS in Drosophila and primary cortical neurons. The public health relevance of this project lies in the fact that ALS is a fatal disease with no cures and only one, marginally effective, treatment. The work presented here addresses this issue by highlighting pathways that are affiliated with disease pathology, and identifying modifiers of toxicity that may be useful as future therapeutic targets." @default.
• W2769364032 created "2017-12-04" @default.
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• W2769364032 date "2017-08-31" @default.
• W2769364032 modified "2023-09-27" @default.
• W2769364032 title "Identifying novel modifiers of FUS-associated toxicity in a Drosophila model of amyotrophic lateral sclerosis" @default.
• W2769364032 hasPublicationYear "2017" @default.
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