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Identifying the right mouse model for Huntington’s disease drug development

Scientists have evaluated mouse models used for developing treatments for mood disorders associated with Huntington’s disease and have recommended which have greater potential for success. 

white lab mouse on blue gloved hands

Scientists have evaluated mouse models used for developing new treatments for mood disorders associated with Huntington’s disease (HD) and have recommended which are most relevant and have greater potential for success. 

“Patients with HD commonly suffer from debilitating mood disorders, but developing disease-modifying drugs for HD has proved to be extremely challenging,” explained lead investigator Robert M Friedlander, MD, MA, Chair and Walter E. Dandy Professor of Neurosurgery and Neurobiology at University of Pittsburgh School of Medicine and Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh. “One reason could be that we are not using the right animal models in research.”

The amount of serotonin transporter (SERT), a molecule commonly targeted by medications to regulate mood, is increased in the brain of patients with HD. Investigators compared SERT levels in normal and Huntington’s brain tissue samples, as well as brain tissues from two different mouse models of the disease. They found that the amount of SERT was increased in HD patients compared with controls and that this finding was modeled in one type of mouse model, but not another.

Investigators found that HD patients have significantly increased SERT protein levels in one region of the brain, the striatum, which co-ordinates multiple aspects of cognition, but not in the globus pallidus, which regulates voluntary movement. The neurodegenerative process commences in and most severely affects the striatum, affecting other brain regions as the disease progresses. This likely has an impact on the prevalent mood disorder in HD. Increased SERT levels are demonstrated in the brain of CAG140 mice, a full-length knock-in mouse model of the disease, but not in the striatum of the R6/2 fragment murine model of the disease.

…the amount of SERT was increased in HD patients compared with controls”

Based on this parameter, the investigators recommend that the CAG140 huntingtin knock-in mouse model is more suitable than the R6/2 model for the study of serotonergic pathway pathology in HD. The team say that this is important because researchers should be sure to use the appropriate disease models when designing experiments. However, they conclude, there is no mouse model that completely recapitulates human HD. 

“We found that not all HD mouse models are the same, so researchers need to use the models that are most relevant to their studies,” Dr Friedlander continued. “This advance in our understanding of the mood-related symptoms in HD is key to designing treatments that will improve the quality of life for patients with this disease.”

The results were reported in the Journal of Huntington’s Disease.

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