Selecting Right Mouse Model Key for Huntington’s Research, Therapy Development, Study Finds

Certain aspects of Huntington’s disease (HD), such as the biologic mechanisms of depression, are not consistently replicated in mouse models of the disorder, which may hinder therapy development, a study reports.

The study, “Increased Serotonin Transporter Expression in Huntington’s Disease Patients Is Not Consistently Replicated in Murine Models,” was published in the Journal of Huntington’s Disease.

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

Serotonin, sometimes called the “happy” brain chemical due to its contribution to the feeling of general well-being and happiness, is a key regulator of mood and is associated with cognitive function. The serotonin transporter (SERT) is the “recycling device” that pulls serotonin back in from the space between neurons, or the synaptic cleft, for reuse. Nerve cells communicate with each other by releasing molecules into this synaptic cleft.

In depression, SERTs are overly active and remove most of the serotonin between neurons, contributing to the characteristic feelings associated with depression.

Studies have shown there is an increase in the levels of SERT in the striatum of patients with Huntington’s disease. The striatum is a brain region involved in the regulation of voluntary movement, cognition, and reward processes, and is significantly damaged in Huntington’s.

Selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, inhibit SERT function and allow serotonin to stay for a longer period of time in the synapse. SSRIs can not only alleviate the psychiatric symptoms in Huntington’s disease patients, but also delay neurodegeneration by increasing neurogenesis — the production of neurons from neural stem cells.

However, SERT levels in Huntington’s disease have not been extensively evaluated in patients or mouse models.

Friedlander and his colleagues at the University of Pittsburgh set out to quantify SERT levels in Huntington’s patients and mouse models of the disease. To do so, they used brain striatal and globus pallidus — a brain region also involved in the regulation of voluntary movement — samples from 11 Huntington’s patients (five men and six women; ages 36–82) as well as brain tissue from two distinct mouse models, called CAG140 and R6/2.

Huntington’s disease is caused by excessive repeats (more than 35) of a portion of DNA, called CAG triplets, within the huntingtin (HTT) gene. CAG140 mice genetically replicate the disorder by having 140 CAG repeats within their HTT gene, while the R6/2 mice used in this study had about 150 repeats.

Researchers found that SERT protein levels were significantly increased in the striatum of patients who had grade 4, or the most severe form, of Huntington’s. In addition, no SERT level changes were observed in the patients’ globus pallidus. However, levels of SERT mRNA — the template that provides instructions to produce a protein — remained unchanged across disease grades and compared with control subjects.

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, several complex steps exist before a protein can be produced: DNA is first transformed into mRNA, and eventually, into a protein. Thus, elevated SERT levels without changes in mRNA suggests there may be a dysregulation after SERT mRNA is generated and before the corresponding SERT protein is produced. Importantly, this dysregulation could be a contributing factor regulating depression in Huntington’s patients.

When scientists analyzed mouse data, they found that these increased striatal SERT protein levels were only replicated in the CAG140 mouse model.

Although there is no animal model that fully mimics human Huntington’s disease, the team suggested that the CAG140 mouse may be more appropriate for studying serotonin signaling in Huntington’s disease.

“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. 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,” Friedlander said.