Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations

Finelli, M. J.; Liu, K. X.; Wu, Y.; Oliver, P. L.; Davies, K. E.

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.

Citation

Finelli, M. J., Liu, K. X., Wu, Y., Oliver, P. L., & Davies, K. E. (2015). Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations. Human Molecular Genetics, 24(12), 3529-3544. https://doi.org/10.1093/hmg/ddv104

• Journal Article Type: Article
• Acceptance Date: Mar 16, 2015
• Online Publication Date: Mar 19, 2015
• Publication Date: Jun 15, 2015
• Deposit Date: Jul 25, 2021
• Publicly Available Date: Jul 26, 2021
• Journal: Human Molecular Genetics
• Print ISSN: 0964-6906
• Electronic ISSN: 1460-2083
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 12
• Pages: 3529-3544
• DOI: https://doi.org/10.1093/hmg/ddv104
• Keywords: Genetics(clinical); Genetics; Molecular Biology; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/5832650
• Publisher URL: https://academic.oup.com/hmg/article/24/12/3529/623195