title: Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations.
abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43 kDa (TDP-43), are responsible for 5-10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration. Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently, we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1-binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp-43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localization and aggregation, splicing changes of a mitochondrial gene and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology.
authors: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors: Mattéa J
authors: MJ
authors: Finelli
authors: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors: Kevin X
authors: KX
authors: Liu
authors: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors: Yixing
authors: Y
authors: Wu
authors: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK kay.davies@dpag.ox.ac.uk peter.oliver@dpag.ox.ac.uk.
authors: Peter L
authors: PL
authors: Oliver
authors: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK kay.davies@dpag.ox.ac.uk peter.oliver@dpag.ox.ac.uk.
authors: Kay E
authors: KE
authors: Davies
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism; D001343:Autophagy / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D008745:Methylation; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D059748:Proteolysis; D012326:RNA Splicing; D034702:RNA-Binding Protein FUS / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; C419777:OXR1 protein, human; D020033:Protein Isoforms; D011506:Proteins; D034702:RNA-Binding Protein FUS; D001120:Arginine; D046988:Proteasome Endopeptidase Complex