Suppressing Ataxin-2 Protein Extended Survival Rate in ALS Mice Study

Suppressing the expression of a protein called ataxin-2 may prolong survival in patients with amyotrophic lateral sclerosis (ALS), according to a recent mouse study.

The study, “Therapeutic Reduction Of Ataxin-2 Extends Lifespan And Reduces Pathology In TDP-43 Mice,” was published in the journal Nature.

According to researchers, nearly all ALS patients have aggregates of a protein called TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding this protein can trigger ALS. However, TDP-43 cannot be eliminated in neurons because it plays several important functions in neuronal survival.

A research team led by Aaron Gitler, PhD, from the Stanford University School of Medicine, developed a way to fight the toxic effect of TDP-43 aggregates without completely eliminating the protein from the brain.

Their work was based on previous findings that when the protein ataxin-2 is absent, it helped neurons survive in the presence of human TDP-43 aggregates in yeast and flies, and that the human form of ataxin-2, which is more stable and lasts longer in neurons, increased the risk of ALS. Researchers then hypothesized that reducing ataxin-2 levels could protect neurons in ALS.

They tested their idea using genetically altered mice that produce high levels of the human TDP-43 protein, that present symptoms resembling human ALS, and live no more than one month. These animals were then altered to have half the normal amount of ataxin-2, or none at all.

The decrease in ataxin-2 reduced aggregation of TDP-43 markedly increased survival and improved motor function in the mice.

“But what was really astounding,” Lindsay Becker, study’s first author, said in a press release, “was that when we completely removed ataxin-2, there was really an unprecedented survival; some of the mice lived hundreds and hundreds of days.”

The team then used a more therapeutically applicable approach to target ataxin-2. They administered antisense oligonucleotides (ASOs, tiny molecules that block the expression of specific proteins) against ataxin-2 to TDP-43 mice, and observed that a single treatment markedly extended survival.

Together, these results suggest that targeting ataxin-2 could represent a broadly effective therapeutic strategy, as nearly all ALS patients have TDP-43 toxic aggregation in their neurons.

According to Becker, the team’s next step is to test whether ASOs or other protein-blocking treatments can reverse symptoms in mice in which the disease already has developed.