Mouse Model Developed for Common Form of ALS, Frontotemporal Dementia

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Researchers from Mayo Clinic have created a mouse model that exhibits the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), caused by a mutation in the C9ORF72 gene.

The repeat expansion of the C9ORF72, a genetic abnormality, leads to the generation of toxic RNA that form abnormal foci and inclusions of c9RAN and TDP-43 proteins. The TDP-43 proteins have long been understood to misbehave in both ALS and FTD, as well as Alzheimer's and in patients with repeated head injury, however this latest study sheds light on the little known connection between TDP-43 and C9ORF72 repeat expansion.

“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,” said Leonard Petrucelli, PhD, of Mayo Clinic in Florida. “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.”

The researchers believe that the C9ORF72 repeat expansion may be behind the behavioral changes and motor skill impairments observed in ALS and FTD patients. Mice who expressed the repeat expansion showed hyperactivity, anxiety, antisocial behavior, and motor deficits.

Mayo Clinic researchers are now collaborating with a team from the Scripps Research Institute in Florida to identify compounds that bind to the repeat expansion RNA before it forms foci and c9RAN proteins that damage nerve function. The mouse model is pivotal in helping identify a compound since initial findings indicate that alleviating toxicity linked to the foci and c9RAN proteins also prevents TDP-43 pathology. By targeting the RNA, the researchers hope to combat cell death and disease symptoms.

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