Scientists create mice with genetic cause of amyotrophic lateral sclerosis, frontotemporal dementia

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May 22, 2015

Scientists at Mayo Clinic, Jacksonville, Florida created a novel mouse that exhibits the symptoms and neurodegeneration associated with the most common genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both of which are caused by a mutation in the gene C9ORF72. The study was partially funded by the National Institutes of Health and published in the journal Science.

"Our mouse model exhibits the pathologies and symptoms of ALS and FTD seen in patients with the C9ORF72 mutation," said the study's lead author, Leonard Petrucelli PhD, chair and Ralph and Ruth Abrams Professor of the Department of Neuroscience at Mayo Clinic, and a senior author of the study. "These mice could greatly improve our understanding of ALS and FTD and hasten the development of effective treatments."

To create the model, Ms Jeannie Chew, a Mayo Graduate School student and member of Dr Petrucelli's team, injected the brains of newborn mice with a disease-causing version of the C9ORF72 gene. As the mice aged, they became hyperactive, anxious, and antisocial, in addition to having problems with movement that mirrored patient symptoms. The brains of the mice were smaller than normal and had fewer neurons in areas that controlled the affected behaviors. The scientists also found that the mouse brains had key hallmarks of the disorders, including toxic clusters of ribonucleic acids (RNA) and TDP-43, a protein that has long been known to go awry in the majority of ALS and FTD cases.

"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," said Margaret Sutherland PhD, program director, the National Institute of Neurological Disorders and Stroke, part of NIH. "This mouse model will be a valuable tool for developing therapies for these devastating disorders."

The C9ORF72 gene is encoded by repeating strings of 6 DNA molecules. Disease-causing C9ORF72 mutations make the strings excessively long, which leads to the accumulation of RNA that either cluster into foci or cause the production of abnormal c9RAN proteins in the brain and spinal cord of patients. The scientists found both in the brains of the mice. They also found inclusions of TDP-43 protein, another pathological hallmark found in patients with the C9ORF72 mutation.

"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 think these results are an important step in the development of therapies for these forms of ALS and FTD and other neurodegenerative disorders.

This work was supported by grants from NIH (NS089979, NS084528, NS079807, NS088689, NS063964, NS077402, NS084974, AG016574, ES20395), Department of Defense (ALSRP AL130125), Mayo Clinic Foundation, Mayo Clinic Center for Regenerative Medicine, Mayo Graduate School, ALS Association, Robert Packard Center for ALS Research at Johns Hopkins, Target ALS, and Alzheimer's Association (NIRP-14-304425, NIRP-12-259289).

Source: News Release
NIH/NINDS
May 22, 2015

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