title: Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.
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.
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.|Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Becker
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Huang
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.|Stanford Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bieri
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Ma
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.|Department of Radiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Knowles
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Paymaan
authors.initials: P
authors.lastname: Jafar-Nejad
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: James
authors.initials: J
authors.lastname: Messing
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Hong Joo
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Armand
authors.initials: A
authors.lastname: Soriano
authors.affiliation: Experimental Neurology, Department of Neurology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Auburger
authors.affiliation: Experimental Neurology, Department of Neurology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pulst
authors.affiliation: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, California 92010, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D000818:Animals; D000067698:Ataxin-2 / Q000172:deficiency* / Q000235:genetics; D002490:Central Nervous System / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008136:Longevity; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000628:therapy*; D013312:Stress, Physiological; D016019:Survival Analysis
chemical_list: D000067698:Ataxin-2; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; C000598624:TARDBP protein, human