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

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Becker, Lindsay A., Huang, Brenda, Bieri, Gregor, Ma, Rosanna, Knowles, David A., Jafar-Nejad, Paymaan, Messing, James, Kim, Hong Joo +6 more·2017·Nature
DOI 10.1038/nature22038PMC PMC5642042
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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.

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  • Pathological TDP-43 aggregation and premature polyadenylation and loss of stathmin-2 are pathologies commonly observed across sALS and fALS.

    “alternative approaches that mitigate pathologies commonly observed across sALS and fALS, such as pathological TDP-43 aggregation (39) or premature polyadenylation and loss of stathmin-2, a key regulator of microtubule dynamics in motor neurons (55, 56), are highly desirable.”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [39]

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Research works printed but not linked: 31

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Authors
Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., & Gitler, A. D.
Affiliations
  • Stanford Medicine (US)
  • St. Jude Children's Research Hospital (US)
  • Ionis Pharmaceuticals (United States) (US)
  • Goethe University Frankfurt (DE)
Corresponding author
Gitler, Aaron D.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2017-04-12
Volume
544
Issue
7650
Pages
367-371
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature22038
PMC
PMC5642042
OpenAlex
W2606848380
Cited by
571
References
3
Citations by year
2026: 41 · 2025: 64 · 2024: 60 · 2023: 59 · 2022: 56 · 2021: 55 · 2020: 61 · 2019: 68 · 2018: 76 · 2017: 28 · 2015: 1
FWCI
44.39
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (T32AG047126)
  • National Institute of Neurological Disorders and Stroke (R01NS073660, R35NS097974, R21NS081182, P30NS069375, R01NS065317, R01NS097903, R37NS033123, R35NS097263)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
ATXN2, TDP-43, amyotrophic lateral sclerosis, spinocerebellar ataxia type 2, antisense oligonucleotides, TDP-43 aggregation, lifespan extension, motor function, Purkinje cells, neurodegeneration, RNA-binding proteins, transgenic mouse model
MeSH terms
Ataxin-2, Amyotrophic Lateral Sclerosis, Animals, Central Nervous System, Cytoplasmic Granules, DNA-Binding Proteins, Female, Humans, Longevity, Male, Mice, Transgenic, Motor Skills, Stress, Physiological, Survival Analysis, Oligonucleotides, Antisense, Mice, Knockout, Disease Progression, Mice, Gene Knockdown Techniques, Protein Aggregation, Pathological

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