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Nature. 2017 Apr 20;544(7650):367-371. doi: 10.1038/nature22038. Epub 2017 Apr 12.

Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.

Author information

1
Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
2
Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, California 94305, USA.
3
Department of Radiology, Stanford University School of Medicine, Stanford, California 94305, USA.
4
Ionis Pharmaceuticals, Carlsbad, California 92010, USA.
5
Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
6
Experimental Neurology, Department of Neurology, Goethe University, 60590 Frankfurt am Main, Germany.
7
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2-5 years after disease onset. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause ALS. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases. Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression. However, as SOD1 mutations account for only around 2-5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions. Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS. We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy. First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function. Second, in a more therapeutically applicable approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy.

PMID:
28405022
PMCID:
PMC5642042
DOI:
10.1038/nature22038
[Indexed for MEDLINE]
Free PMC Article

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