Study On Suppressed Ataxin-2 Gives ALS Patients Hope Of Survival

The ALS Association defines ALS, Amyotrophic Lateral Sclerosis, as “a neurodegenerative disease that affects nerve cells in the brain and the spinal cord”. It is a condition where the muscles of the body do not get enough nourishment making them waste away or atrophy. This leads to the scarring or hardening of the affected muscles.

ALS is caused by the degeneration and eventual death of the motor neurons coming from the spinal cord to the muscles. Once the neurons are dead, the brain is unable to control or initiate voluntary muscle movement and control. The prognosis for ALS is usually bleak with an expected lifespan of two to five years from disease onset.

Majority of the ALS cases are associated with the presence of RNA-binding protein TDP-43 in their brains and spinal cords. Scientists have found that rare mutations in the gene encoding TDP-43 can cause ALS. However, there have been no known effective TDP-43 directed therapies for ALS until a recent study published in the journal Nature.

The researchers studied the response of genetically altered mice with inherited ALS, presence of TDP-43, after reducing ataxin-2 levels. They found that by reducing ataxin-2, TDP-43 levels also decreased leading to increased survival and improved motor function. Suppressing TDP-43 entirely would seem like a good strategy but its complete elimination would hurt the neurons’ survival. A research team from Stanford University School of Medicine have found a way of countering the toxicity of the protein TDP-43 without completely eliminating it from the neurons.

In the study, the team led by Dr. Aaron Gitler, based their work on previous findings; the absence of ataxin-2 helped neurons survive TDP-43 aggregates in yeast and flies similar to those found in humans. They also deduced that the more stable and long-lasting human form of ataxin-2 increased the risk of ALS. Based on this, they inferred that a decrease in ataxin-2 levels could protect neurons in ALS.

This hypothesis was tested on genetically altered mice with high levels of human TDP-43 protein. They also exhibited symptoms similar to human ALS and would live no more than one month. The population was divided into two: those whose gene was altered to half the normal amount of ataxin-2 and those who completely lacked the protein.

The reduced ataxin-2 aggregation of TDP-43 significantly increased survival rates and improved motor function in the mice. The outcome was phenomenal for the mice that completely lacked the protein. According to Becker, “But what was astounding 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 tried treating mice with a DNA-like drug, antisense oligonucleitodes, designed to block ataxin-2. The antisense oligonucleitodes when delivered to the nervous system of the ALS mice, the mice’s health was maintained for longer than those treated with a placebo.

With nearly all ALS patients having the TDP-43 protein in their neurons, this study showed that targeting Ataxin-2 would be a suitable therapy for ALS patients. The next step for the team is to study how to reverse the ALS symptoms in mice.