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.
Highlights
Amyotrophic lateral sclerosis (ALS) is characterised by the progressive loss of upper motor neurons in the cerebral cortex and lower motor neurons in the brainstem and spinal cord, leading to severe muscle wasting and death due to respiratory failure [1]
To investigate whether oxidation resistance 1 (Oxr1) is a genetic modifier of this key transactive response DNA-binding protein 43 kDa (TDP-43)-associated phenotype, homozygous TDP-43M337V/M337V mice were crossed with mice hemizygous for a full-length Oxr1 cDNA transgene driven by a neuronal promoter (Oxr1Prnp/-) [21]
Consistent with previous observations [33], a significant proportion of mutant TDP-43 was detected in the cytoplasm of motor neurons from TDP-43M337V/- mice, interestingly this proportion was significantly reduced in TDP-43M337V/-/Oxr1Prnp/- cells (Figure 1B; p=0.0007)
Summary
Amyotrophic lateral sclerosis (ALS) is characterised by the progressive loss of upper motor neurons in the cerebral cortex and lower motor neurons in the brainstem and spinal cord, leading to severe muscle wasting and death due to respiratory failure [1]. ALS is understood to have a complex etiology, with mutations in more than 20 genes associated with both familial and some apparently sporadic forms; no identified genetic contribution has been identified in the majority (~85%) of cases. Despite this heterogeneity, over 95% of all ALS cases share the pathological signature of mislocalised TDP-43 (43-kDa transactive response DNA-binding protein) [2,3]. Mutations in the TARDBP gene, encoding TDP-43, account for approximately 5% of familial ALS (fALS), less than 1% of sporadic ALS (sALS), as well as rare familial cases of frontotemporal dementia [5,6,7,8]. Genetic studies have revealed over 50 mutations in TDP-43 [9] and the majority are clustered in the glycine-rich Cterminal domain [10]
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