Researchers at the Jacksonville, Florida Mayo Clinic have gained a mouse model for testing potential amyotrophic lateral sclerosis (ALS) treatments. ALS or Lou Gehrig's disease is associated with various behavioral features and neuropathological symptoms as is frontotemporal dementia (FTD); both are caused by a mutation in the C9ORF72 gene. Both result in the death of neurons in the spinal cord and brain, which leads to inability to control muscles, paralysis, and death.

The team expects that these results will hasten research into the molecular mechanism for ALS and FTD, and that potential therapeutic agents can be tested using this animal model.

"Our mouse model exhibits the pathologies and symptoms of ALS and FTD seen in patients with the C9ORF72mutation," chair of the Mayo Clinic Department of Neuroscience in Florida and the study's senior author, Leonard Petrucelli says.

According to the ALS Association, more than 30,000 Americans have ALS. This disease makes walking, speaking, and even swallowing and breathing difficult and, eventually, impossible. FTD is a common form of early onset dementia, second in incidence rate only to Alzheimer's disease. Changes in language, behavior, and personality are symptoms of FTD, which is now believed to make up 10 to 15 percent of all dementia cases.

This mouse model proves that the genetic abnormality of the C9ORF72 repeat expansion causes the formation of abnormal clumps and inclusions of TDP-43 and c9RAN proteins, as it prompts the generation of toxic ribonucleic acid (RNA) species. This is significant because although the proteins were already known, the link between inclusions of the TDP-43 protein which malfunctions in most FTD and ALS cases and the C9ORF72 repeat expansion was not. TDP-43 inclusions are also found in people with repeat concussions, head injuries, and Alzheimer's disease.

The team found that these biochemical and physical changes in the brain of the mice could be responsible for the motor impairments and observed behavioral deficits that are so much like symptoms of the disease in humans. The mice with expanded C9ORF72 repeats throughout their CNS showed symptoms by the time they reached six months old: antisocial behavior, anxiety, hyperactivity, and motor deficits.

"Finding TDP-43 in these mice was entirely unexpected-and we could not have discovered a link between the repeat expansion in C9ORF72 and development of TDP-43 pathology without the mouse model," Petrucelli says. "This is a very exciting observation."

"We don't yet know how foci and c9RAN proteins are linked to TDP-43 abnormalities or what the pathway is, but with our new animal model, we now have a way to find out."

These findings, which will be in the next issue of the journal Science, promise to be a useful tool in drug therapy testing. Recreating the spread of the mutation in mice allowed researchers "to model what happens in human disease quite faithfully," Petrucelli says. "The mice developed all the pathologies you find in the human brain."