New ALS Mouse Model Has Human FUS Mutation

by Amy Madsen on Mon, 2014-02-10 11:45

Researchers say the new model will increase understanding of the role FUS mutations play in ALS and help pinpoint therapeutic targets for FUS-associated ALS

Article Highlights:
  • An MDA-supported research team reports that it has generated the first transgenic mouse model for ALS caused by mutations in the FUS gene.
  • The model carries the most common human FUS mutation, called FUS-R521C, and exhibits characteristics commonly seen in human ALS patients.
  • Researchers say the mouse provides insight on how FUS mutation cause nerve cell death in ALS.
  • The model is expected to help with identification of therapeutic targets for ALS caused by FUS mutations.

A new research mouse model is the first to carry a mutation in the gene for the FUS protein that's known to cause human amyotrophic lateral sclerosis (ALS), an MDA-supported research team reports.

Animal models play a key role in disease research, and researchers say the new FUS model is an important addition to the ALS research toolkit.

The new mouse is expected to increase understanding of how mutations in FUS cause nerve cell death in ALS. In addition it may help scientists identify potential therapeutic targets for ALS caused by FUS mutations.

FUS mouse exhibits characteristics seen in human ALS

MDA-supported Eric J. Huang at the University of California, San Francisco, and colleagues generated mice that carry a flaw (mutation) in the gene for the FUS protein. The mutation, known as FUS-R521C, is the most common FUS mutation known to cause ALS in people.

Mice carrying the flawed FUS gene exhibit abnormalities commonly seen in human ALS patients with the same mutation, such as DNA damage and defects in spinal motor neurons and nerve cells in the brain that play a role in thought, perception and voluntary movement.

In addition, the mice have slowed growth and shortened life span. Abnormalities in motor function include severe muscle tightness in the limbs, muscle atrophy (reduced muscle mass), coordination problems and abnormal gait.

Studies in the new mouse provide insight to nerve cell death in ALS

In further studies, the research team noted that the DNA damage repair process and RNA processing are negatively affected in mice carrying the FUS mutation. Disruption of these processes — both critical mechanisms for proper cell function — have been implicated in the degeneration and death of nerve cells.

Another possible explanation for nerve cell death observed in the mice was increased activity in the spinal cord of genes that are functionally associated with immune response and activation of the complement pathway — both areas of which are thought to contribute to the ALS disease process.

The findings may help guide scientists in the search for specific targets at which to direct therapies.

The team reported its findings online, Feb. 10, 2014, in the Journal of Clinical Investigation. See ALS-Associated Mutation FUS-R521C Causes DNA Damage and RNA Splicing Defects.

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