Scientists created a mouse model of ALS and FTD caused by mutations in the C9ORF72 gene.[Courtesy of Petrucelli lab, Mayo Clinic, Jacksonville, Fla.]
Scientists created a mouse model of ALS and FTD caused by mutations in the C9ORF72 gene.[Courtesy of Petrucelli lab, Mayo Clinic, Jacksonville, Fla.]

Improving animal models for various disease states has been a thorn in the side of scientists for decades. Recapitulating both genotypic and phenotypic traits has been daunting, especially for neurodegenerative disorders, where researchers are just beginning to unlock the molecular underpinnings of the pathological conditions. However, researchers at the Mayo Clinical in Jacksonville have just recently generated a mouse that exhibits the symptoms and neurodegeneration associated with the most common forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), caused by mutations in the C9ORF72 gene—potentially providing a new platform for testing treatments aimed at these neurological conditions.

As many as 30,000 people in the US are affected with ALS, which destroys the neurons that control speaking, walking, breathing, and swallowing. Moreover, after Alzheimer’s disease, FTD is the most common form of earl onset dementia, characterized by changes in personality, behavior, and language. Consequently, patients with mutations in the C9ORF72 gene can exhibit some or all of the symptoms associated with both neurologic disorders.  

“Our mouse model exhibits the pathologies and symptoms of ALS and FTD seen in patients with the C9ORF72 mutation,” explains Leonard Petrucelli, Ph.D., chair and Ralph and Ruth Abrams Professor of the Department of Neuroscience at Mayo Clinic, and senior author on the current study. “These mice could greatly improve our understanding of ALS and FTD and hasten the development of effective treatments.”

The findings from this study were published recently in Science through an article entitled “C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits.”

Dr. Petrucelli’s team created the mice by injecting the brain of newborn pups with a mutated form of the C9ORF72 gene. As the mice aged, they began to present with symptoms that are typically observed in many human patients such as, hyperactivity, anxiousness, movement disorders and antisocial behavior. Additionally, the brains of the injected mice were smaller and had fewer neurons in brain regions that controlled the affected behaviors. Furthermore, the Mayo team identified key molecular hallmarks of the neurologic disorders, including toxic clusters of RNA and TDP-43—a protein known for its aberrant activity in ALD and FTD cases.     

The mutated C9ORF72 gene arises due to a nucleotide repeat expansion of cytosine and guanine residues within the gene coding region. The long expansion of this gene can either lead to the accumulation of RNA into clusters called foci or the production of an abnormal protein called c9RAN within the brain and spinal cords of afflicted patients.  

“Finding TDP-43 in these mice was unexpected” Dr. Petrucelli said. “We don't yet know how foci and c9RAN proteins are linked to TDP-43 abnormalities, but with our new animal model, we now have a way to find out.”

Dr. Petrucelli and his team are excited about the results from their new mouse model and feel that it is an important step forward toward the development of potential novel therapies for FTD and ALS.

“This is a significant advancement for the field. Scientists have been trying to create mice that accurately mimic the pathologies associated with these forms of ALS and FTD,” stated Margaret Sutherland, Ph.D., program director at the National Institute of Neurological Disorders and Stroke. “This mouse model will be a valuable tool for developing therapies for these devastating disorders.”

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