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 onset1. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords2, and rare mutations in the gene encoding TDP-43 can cause ALS3. 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 diseases4. 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 progression5. 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 functions1,6. 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 flies7, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS7,8. We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy9. 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 ALS6, targeting ataxin-2 could represent a broadly effective therapeutic strategy.
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This work was supported by NIH grants R01NS065317, R01NS09386501, R01NS073660 and R35NS097263 (10) (A.D.G.), NIH grant R35NS097974 (J.P.T), HHMI (J.P.T), NIH grants R21NS081182 and R37NS033123 (S.M.P), the National Science Foundation Graduate Research Fellowship (L.A.B.), the Robert Packard Center for ALS Research at Johns Hopkins (A.D.G.), Target ALS (A.D.G.), the Glenn Foundation (A.D.G.), and the DFG grant AU96/13-1 (G.A.). We thank L. Petrucelli and V. Lee for sharing TDP-43 antibodies, J. Shorter and L. Petrucelli for comments on the manuscript and discussions, A. Olsen and the Stanford Neuroscience Microscopy Service, supported by a grant from NIH (NS069375), for help with the confocal images, Y. Zuber (Stanford Veterinary Service Center) for mouse husbandry advice and support, Stanford’s Human Immune Monitoring Center (HIMC) for performing the Luminex assays.
Extended data figures
This mouse was given a gait impairment score of 0.
This mouse was given a gait impairment score of 1.
This mouse was 21 days old and given a gait impairment score of 3 as it had very limited hindlimb joint movement and falls over.
This mouse was 22 days old and given a gait impairment score of 4 (humane euthanasia endpoint) because it was unable to right itself within 30 seconds of falling on its side on all 3 of 3 trials.
This TDP-43Tg/TgAtxn2–/– mouse was at 61 days old and still had no overt motor impairment. It was therefore given a gait impairment score of 0.
Examples of three P20 TDP-43Tg/Tg that received intracerebroventricular (ICV) administration of either the control ASO or the Atxn2 ASO at P1. The two severely impaired mice (gait impairment score of 4), which were unable to right themselves, received the control ASO whereas the one unimpaired mouse received the Atxn2 ASO.