Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Becker, L. A., Huang, B., Bieri, G., Ma, R., <b>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. Nature, 544(7650):367--371, 2017.
Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice [link]Paper  doi  abstract   bibtex   
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. To test the hypothesis that a decrease in ataxin-2 levels can res-cue neurodegenerative phenotypes caused by TDP-43 accumula-tion, we first used a genetic approach. There are several transgenic mouse lines that express wild-type or mutant TDP-43, using various strategies 10
@article{Becker2017,
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 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. To test the hypothesis that a decrease in ataxin-2 levels can res-cue neurodegenerative phenotypes caused by TDP-43 accumula-tion, we first used a genetic approach. There are several transgenic mouse lines that express wild-type or mutant TDP-43, using various strategies 10},
author = {Becker, Lindsay A. and Huang, Brenda and Bieri, Gregor and Ma, Rosanna and <b>Knowles, David A.</b> and Jafar-Nejad, Paymaan and Messing, James and Kim, Hong Joo and Soriano, Armand and Auburger, Georg and Pulst, Stefan M. and Taylor, J. Paul and Rigo, Frank and Gitler, Aaron D.},
doi = {10.1038/nature22038},
issn = {0028-0836},
journal = {Nature},
keywords = {Biology, Genetics, Statistics},
number = {7650},
pages = {367--371},
pmid = {28405022},
title = {{Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice}},
url = {http://www.nature.com/doifinder/10.1038/nature22038},
volume = {544},
year = {2017}
}
Downloads: 0
About
Documentation
Keywords
Search
Users
Terms and Conditions of Use
Privacy Policy
Sitemap
© BibBase.org 2021