Version history

{
  "pmid": "28405022",
  "doi": "10.1038/nature22038",
  "abstract": "1. Nature. 2017 Apr 20;544(7650):367-371. doi: 10.1038/nature22038. Epub 2017 Apr\n 12.\n\nTherapeutic reduction of ataxin-2 extends lifespan and reduces pathology in \nTDP-43 mice.\n\nBecker LA(1)(2), Huang B(1), Bieri G(1)(2), Ma R(1), Knowles DA(1)(3), \nJafar-Nejad P(4), Messing J(5), Kim HJ(5), Soriano A(4), Auburger G(6), Pulst \nSM(6), Taylor JP(5)(7), Rigo F(4), Gitler AD(1).\n\nAuthor information:\n(1)Department of Genetics, Stanford University School of Medicine, Stanford, \nCalifornia 94305, USA.\n(2)Stanford Neurosciences Graduate Program, Stanford University School of \nMedicine, Stanford, California 94305, USA.\n(3)Department of Radiology, Stanford University School of Medicine, Stanford, \nCalifornia 94305, USA.\n(4)Ionis Pharmaceuticals, Carlsbad, California 92010, USA.\n(5)Department of Cell and Molecular Biology, St. Jude Children's Research \nHospital, Memphis, Tennessee 38105, USA.\n(6)Experimental Neurology, Department of Neurology, Goethe University, 60590 \nFrankfurt am Main, Germany.\n(7)Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.\n\nComment in\n    Nature. 2017 Apr 20;544(7650):302-303. doi: 10.1038/nature21911.\n    Nat Rev Drug Discov. 2017 Jun;16(6):384-385. doi: 10.1038/nrd.2017.104.\n    Nat Rev Mol Cell Biol. 2019 Feb;20(2):67. doi: 10.1038/s41580-018-0062-6.\n\nAmyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative \ndisease that is characterized by motor neuron loss and that leads to paralysis \nand death 2-5 years after disease onset. Nearly all patients with ALS have \naggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, \nand rare mutations in the gene encoding TDP-43 can cause ALS. There are no \neffective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, \nsuch as frontotemporal dementia. Antisense oligonucleotides (ASOs) and \nRNA-interference approaches are emerging as attractive therapeutic strategies in \nneurological diseases. Indeed, treatment of a rat model of inherited ALS (caused \nby a mutation in Sod1) with ASOs against Sod1 has been shown to substantially \nslow disease progression. However, as SOD1 mutations account for only around \n2-5% of ALS cases, additional therapeutic strategies are needed. Silencing \nTDP-43 itself is probably not appropriate, given its critical cellular \nfunctions. Here we present a promising alternative therapeutic strategy for ALS \nthat involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 \ntoxicity in yeast and flies, and intermediate-length polyglutamine expansions in \nthe ataxin-2 gene increase risk of ALS. We used two independent approaches to \ntest whether decreasing ataxin-2 levels could mitigate disease in a mouse model \nof TDP-43 proteinopathy. First, we crossed ataxin-2 knockout mice with TDP-43 \n(also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced \naggregation of TDP-43, markedly increased survival and improved motor function. \nSecond, in a more therapeutically applicable approach, we administered ASOs \ntargeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This \nsingle treatment markedly extended survival. Because TDP-43 aggregation is a \ncomponent of nearly all cases of ALS, targeting ataxin-2 could represent a \nbroadly effective therapeutic strategy.\n\nDOI: 10.1038/nature22038\nPMCID: PMC5642042\nPMID: 28405022 [Indexed for MEDLINE]\n\nConflict of interest statement: P.J.-N., A.S. and F.R. are employed by Ionis \nPharmaceuticals, a for-profit company that develops ASO therapies. The other \nauthors declare no competing financial interest.",
  "journal": "Nature",
  "year": 2017,
  "authors": "Becker LA, Huang B, Bieri G, Ma R, Knowles DA, Jafar-Nejad P, Messing J, Kim HJ, Soriano A, Auburger G",
  "url": "https://pubmed.ncbi.nlm.nih.gov/28405022",
  "external_ids": {
    "doi": "10.1038/nature22038",
    "pmid": "28405022"
  },
  "citation_count": 1,
  "domain": "neurodegeneration"
}