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

• Published in: Nature (London) Vol. 544; no. 7650; pp. 367 - 371
• Main Authors: Becker, Lindsay A., Huang, Brenda, Bieri, Gregor, Ma, Rosanna, Knowles, David A., Jafar-Nejad, Paymaan, Messing, James, Kim, Hong Joo, Soriano, Armand, Auburger, Georg, Pulst, Stefan M., Taylor, J. Paul, Rigo, Frank, Gitler, Aaron D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.04.2017; Nature Publishing Group
• Subjects: 631/378/1689/132; 631/378/1689/364; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Amyotrophic Lateral Sclerosis - therapy; Animals; Ataxin-2 - deficiency; Ataxin-2 - genetics; Central nervous system; Central Nervous System - metabolism; Cytoplasmic Granules - metabolism; Dementia; Disease Progression; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Gene Knockdown Techniques; Humanities and Social Sciences; Humans; Hypotheses; letter; Longevity; Male; Mice; Mice, Knockout; Mice, Transgenic; Motor Skills - physiology; multidisciplinary; Mutation; Nervous system; Neurodegeneration; Neurons; Oligonucleotides, Antisense - administration & dosage; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - therapeutic use; Pathology; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - therapy; Proteins; Recruitment; Rodents; Science; Stress, Physiological; Survival Analysis; Transgenic animals
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature22038

A decrease in ataxin-2 levels leads to a reduction in the aggregation of TDP-43, markedly increased lifespan and improved motor function in a transgenic mouse model of TDP-43 proteinopathy. Neurodegeneration therapy Ataxin-2 polyglutamine expansions increase the risk for amyotrophic lateral sclerosis (ALS) and cause spinocerebellar ataxia type 2 (SCA2), two neurodegenerative diseases without a cure. A pair of papers this week report therapeutic approaches towards reducing ataxin-2. Nearly all ALS patients have toxic aggregates of the protein TDP-43 in the brain and spinal cord. Lowering ataxin-2 has been shown to suppress TDP-43 toxicity in yeast and flies, and Lindsay Becker et al . now show that lowering ataxin-2 in mice, genetically or with antisense oligonucleotides, reduces TDP-43 aggregation and toxicity, improves motor function and increases lifespan. Elsewhere in this issue, Daniel Scoles et al . test antisense oligonucleotides (ASOs) against ataxin-2 in mice models of SCA2 that recreate progressive adult-onset dysfunction and degeneration of the neuronal network. The most promising therapeutic lead is ASO7, which downregulates ATXN2 mRNA and protein and delays the onset of SCA2 phenotypes. Moreover, treatment of symptomatic mice normalizes firing of cerebellar Purkinje cells and improves motor functioning. Both papers suggest that antisense oligonucleotide-based therapeutic approaches could be used to tackle neurodegeneration. 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 1 . Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords 2 , and rare mutations in the gene encoding TDP-43 can cause ALS 3 . 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 4 . 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 5 . 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 1 , 6 . 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 7 , and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS 7 , 8 . We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy 9 . 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 6 , targeting ataxin-2 could represent a broadly effective therapeutic strategy.