Abstract
Amyotrophic lateral sclerosis (ALS) is a late onset and progressive motor neuron disease. Mutations in the gene coding for fused in sarcoma/translocated in liposarcoma (FUS) are responsible for some cases of both familial and sporadic forms of ALS. The mechanism through which mutations of FUS result in motor neuron degeneration and loss is not known. FUS belongs to the family of TET proteins, which are regulated at the post-translational level by arginine methylation. Here, we investigated the impact of arginine methylation in the pathogenesis of FUS-related ALS. We found that wild type FUS (FUS-WT) specifically interacts with protein arginine methyltransferases 1 and 8 (PRMT1 and PRMT8) and undergoes asymmetric dimethylation in cultured cells. ALS-causing FUS mutants retained the ability to interact with both PRMT1 and PRMT8 and undergo asymmetric dimethylation similar to FUS-WT. Importantly, PRMT1 and PRMT8 localized to mutant FUS-positive inclusion bodies. Pharmacologic inhibition of PRMT1 and PRMT8 activity reduced both the nuclear and cytoplasmic accumulation of FUS-WT and ALS-associated FUS mutants in motor neuron-derived cells and in cells obtained from an ALS patient carrying the R518G mutation. Genetic ablation of the fly homologue of human PRMT1 (DART1) exacerbated the neurodegeneration induced by overexpression of FUS-WT and R521H FUS mutant in a Drosophila model of FUS-related ALS. These results support a role for arginine methylation in the pathogenesis of FUS-related ALS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine / analogs & derivatives
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Adenosine / pharmacology
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Amyotrophic Lateral Sclerosis / genetics
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Amyotrophic Lateral Sclerosis / pathology
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Animals
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Arginine / metabolism
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Cytosol / metabolism
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Disease Models, Animal
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism*
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Drosophila melanogaster / drug effects
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Drosophila melanogaster / enzymology*
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Drosophila melanogaster / genetics
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Enzyme Inhibitors / pharmacology
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Gene Deletion
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Gene Knockdown Techniques
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HEK293 Cells
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Humans
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Inclusion Bodies / drug effects
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Inclusion Bodies / metabolism
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / metabolism*
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Methylation / drug effects
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Methyltransferases / genetics
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Methyltransferases / metabolism*
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Mutant Proteins / metabolism
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Mutation / genetics
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Protein Binding / drug effects
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Protein Transport / drug effects
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Protein-Arginine N-Methyltransferases / antagonists & inhibitors
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Protein-Arginine N-Methyltransferases / metabolism*
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RNA-Binding Protein FUS / metabolism*
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RNA-Binding Protein FUS / toxicity*
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / metabolism*
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Subcellular Fractions / drug effects
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Subcellular Fractions / metabolism
Substances
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Drosophila Proteins
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Enzyme Inhibitors
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Membrane Proteins
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Mutant Proteins
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RNA-Binding Protein FUS
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Repressor Proteins
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periodate-oxidized adenosine
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Arginine
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Art1 protein, Drosophila
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Methyltransferases
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PRMT1 protein, human
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PRMT8 protein, human
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Protein-Arginine N-Methyltransferases
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Adenosine