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

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 onset(1). Nearly all ALS patients contain aggregates of the RNA-binding protein TDP-43 in the brain and spinal cord(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 (FTD). Antisense oligonucleotides (ASOs) and RNA interference approaches are emerging as attractive therapeutic strategies in neurological diseases(4). Indeed, treating a rodent model of inherited ALS (caused by a mutation in SOD1) with ASOs to SOD1 significantly slowed disease progression(5). 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 functions(1,6) 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 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 reducing ataxin 2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy(9). 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 cases(6), targeting ataxin 2 could represent a broadly effective therapeutic strategy.