Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations
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% o...
| Main Authors: | , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Oxford University Press
2015
|
| _version_ | 1826264720991059968 |
|---|---|
| author | Finelli, M Liu, K Wu, Y Oliver, P Davies, K |
| author_facet | Finelli, M Liu, K Wu, Y Oliver, P Davies, K |
| author_sort | Finelli, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T20:12:24Z |
| format | Journal article |
| id | oxford-uuid:2b031ea4-9680-49bc-9cb0-7adc518e91cc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T20:12:24Z |
| publishDate | 2015 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:2b031ea4-9680-49bc-9cb0-7adc518e91cc2022-03-26T12:28:27ZOxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutationsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:2b031ea4-9680-49bc-9cb0-7adc518e91ccEnglishSymplectic Elements at OxfordOxford University Press2015Finelli, MLiu, KWu, YOliver, PDavies, KAmyotrophic 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. |
| spellingShingle | Finelli, M Liu, K Wu, Y Oliver, P Davies, K Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations |
| title | Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations |
| title_full | Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations |
| title_fullStr | Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations |
| title_full_unstemmed | Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations |
| title_short | Oxr1 improves pathogenic cellular features of ALS-associated FUS and TDP-43 mutations |
| title_sort | oxr1 improves pathogenic cellular features of als associated fus and tdp 43 mutations |
| work_keys_str_mv | AT finellim oxr1improvespathogeniccellularfeaturesofalsassociatedfusandtdp43mutations AT liuk oxr1improvespathogeniccellularfeaturesofalsassociatedfusandtdp43mutations AT wuy oxr1improvespathogeniccellularfeaturesofalsassociatedfusandtdp43mutations AT oliverp oxr1improvespathogeniccellularfeaturesofalsassociatedfusandtdp43mutations AT daviesk oxr1improvespathogeniccellularfeaturesofalsassociatedfusandtdp43mutations |