Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo.

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.

• Authors: Matthew G Williamson, Mattéa J Finelli, James N Sleigh, Amy Reddington, David Gordon, Kevin Talbot, Kay E Davies, Peter L Oliver
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 28 Issue 21 Pg. 3584-3599 (11 01 2019) ISSN: 1460-2083 [Electronic] England
• PMID: 31642482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• DNA-Binding Proteins
• Mitochondrial Proteins
• OXR1 protein, human
• TARDBP protein, human

Topics

• Amyotrophic Lateral Sclerosis (genetics, metabolism, pathology, prevention & control)
• Animals
• Cytoplasm (metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Female
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mitochondrial Proteins (genetics, metabolism)
• Motor Neurons (metabolism)
• Muscle Denervation
• Muscles (innervation)
• Mutation, Missense
• Neuromuscular Junction (metabolism)
• Protein Transport