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 characterized by motor neuron loss, leading to paralysis and death 2–5 years following disease onset1. Nearly all ALS patients contain aggregates of the RNA-binding protein TDP-43 in the brain and spinal cord2, 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 (FTD). Antisense oligonucleotides (ASOs) and RNA interference approaches are emerging as attractive therapeutic strategies in neurological diseases4. Indeed, treating a rodent model of inherited ALS (caused by a mutation in SOD1) with ASOs to SOD1 significantly slowed disease progression5. But since SOD1 mutations account for only ~2–5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not warranted given its critical cellular functions1,6 Here we present an unexpectedly powerful alternative therapeutic strategy for ALS, by targeting ataxin 2. Lowering 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 reducing ataxin 2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy9. First, we crossed ataxin 2 knockout mice to TDP-43 transgenic mice. Lowering ataxin 2 reduced TDP-43 aggregation, had a dramatic effect on 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 mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all ALS cases6, targeting ataxin 2 could represent a broadly effective therapeutic strategy.