Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo.
Hum Mol Genet
; 28(21): 3584-3599, 2019 11 01.
Article
em En
| MEDLINE
| ID: mdl-31642482
ABSTRACT
A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization 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 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization 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 harbouring 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 mislocalization 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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Mitocondriais
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Proteínas de Ligação a DNA
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Esclerose Lateral Amiotrófica
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Neurônios Motores
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article