Neuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo
A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia (FTD), is the cellular mislocalisation of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding T...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Oxford University Press
2019
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| _version_ | 1797106175369543680 |
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| author | Williamson, MG Finelli, MJ Sleigh, JN Reddington, A Gordon, D Talbot, K Davies, KE Oliver, PL |
| author_facet | Williamson, MG Finelli, MJ Sleigh, JN Reddington, A Gordon, D Talbot, K Davies, KE Oliver, PL |
| author_sort | Williamson, MG |
| collection | OXFORD |
| description | A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia (FTD), is the cellular mislocalisation of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localisation and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalisation phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harboring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalisation of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes. |
| first_indexed | 2024-03-07T06:58:00Z |
| format | Journal article |
| id | oxford-uuid:fec899dc-3cbe-446a-8ff1-c4ab3479274c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T06:58:00Z |
| publishDate | 2019 |
| publisher | Oxford University Press |
| record_format | dspace |
| spelling | oxford-uuid:fec899dc-3cbe-446a-8ff1-c4ab3479274c2022-03-27T13:39:18ZNeuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivoJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:fec899dc-3cbe-446a-8ff1-c4ab3479274cEnglishSymplectic Elements at OxfordOxford University Press2019Williamson, MGFinelli, MJSleigh, JNReddington, AGordon, DTalbot, KDavies, KEOliver, PLA common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia (FTD), is the cellular mislocalisation of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localisation and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalisation phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harboring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalisation of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes. |
| spellingShingle | Williamson, MG Finelli, MJ Sleigh, JN Reddington, A Gordon, D Talbot, K Davies, KE Oliver, PL Neuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo |
| title | Neuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo |
| title_full | Neuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo |
| title_fullStr | Neuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo |
| title_full_unstemmed | Neuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo |
| title_short | Neuronal over-expression of OXR1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo |
| title_sort | neuronal over expression of oxr1 is protective against als associated mutant tdp 43 mislocalisation in motor neurons and neuromuscular defects in vivo |
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