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

1. 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. Becker LA(1)(2), Huang B(1), Bieri G(1)(2), Ma R(1), Knowles DA(1)(3), Jafar-Nejad P(4), Messing J(5), Kim HJ(5), Soriano A(4), Auburger G(6), Pulst SM(6), Taylor JP(5)(7), Rigo F(4), Gitler AD(1). 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. Comment in Nature. 2017 Apr 20;544(7650):302-303. doi: 10.1038/nature21911. Nat Rev Drug Discov. 2017 Jun;16(6):384-385. doi: 10.1038/nrd.2017.104. Nat Rev Mol Cell Biol. 2019 Feb;20(2):67. doi: 10.1038/s41580-018-0062-6. 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. DOI: 10.1038/nature22038 PMCID: PMC5642042 PMID: 28405022 [Indexed for MEDLINE] Conflict of interest statement: P.J.-N., A.S. and F.R. are employed by Ionis Pharmaceuticals, a for-profit company that develops ASO therapies. The other authors declare no competing financial interest.