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Researchers at UCLA have developed a new mouse model of Huntington’s disease (HD) that better represents this devastating neurological disorder in humans than earlier models and could be a powerful tool for potentially testing new therapies that engage multiple targets as treatment approaches.

The new mouse model, which carries long, uninterrupted CAG repeats in the mutant human huntingtin (mHTT) gene, is providing additional insights into the mystery of how genetic mutations dictate disease onset.

“Our new model is unique from a therapeutic perspective as it has the entire human huntingtin gene, including several DNA variants present in the patients, and it has a long and pure CAG repeat,” said Xiaofeng Gu, PhD, a project scientist in the Center for Neurobehavioral Genetics at the Semel Institute who was primarily responsible for engineering and characterizing the mouse model. The study is published in the journal Cell.

HD is one of the most common autosomal dominant neurodegenerative diseases, and is characterized by progressive movement disorder, cognitive impairment, and psychiatric symptoms, the authors explained. The condition affects more than 30,000 people in the United States, according to the National Institute of Neurological Disorders and Stroke, causing a variety of symptoms, such as personality changes, impaired judgment, unsteady gait and involuntary movements, and speech and swallowing impairment. Although it usually begins between ages 30 and 50, earlier onset (under age 20) or later onset (after age 70) can also occur.

HD is a familial disorder, so a child of parents who both have the disease will have a 50-50 chance of inheriting the causative mutated huntingtin gene. A normal huntingtin gene typically contains about 18 repeats of the DNA letters CAG, but in people with Huntington’s disease the mutated gene may have 40 repeats or many more; the longest stretches found in patients so far contain more than 100 CAG repeats. “HD is caused by a CAG trinucleotide repeat expansion encoding a polyglutamine (polyQ) stretch near the N terminus of huntingtin (HTT),” the team wrote. “Importantly, the age of HD motor disease onset is inversely correlated with the CAG repeat length, a clinical feature shared with other neurodegenerative disorders characterized by CAG repeat and polyQ expansion.”

“Since Huntington’s disease is caused by a single gene mutation, conceivably it should be easier for therapeutic intervention,” Yang noted. “However, even though this mutation was found about 30 years ago and scientists around the world fight very hard to find disease-modifying treatment, so far, all the efforts are yet to be successful, especially with the halting of last year’s promising clinical trial to lower mutant huntingtin expression that was a setback to the HD community.”

The newly reported study by the Yang Lab was designed to answer a genetic mystery in Huntington’s disease. Previous studies in the field had focused on the toxic protein products encoded by the CAG repeats, a string of amino acid residues (glutamine) that are toxic to neurons. However, recent human genetic studies with thousands of HD patients revealed an unexpected finding: Patients with CAA interruptions (CAA also encodes glutamine) in the CAG repeats have a later onset of the disease compared to patients without such interruptions but with the same glutamine repeat.

“Recent genome-wide association studies (GWASs) for modifiers of HD age of onset provide compelling evidence that uninterrupted CAG repeat length, instead of polyQ repeat length, is more closely associated with motor disease onset in HD,” the team further commented. “By examining the presence, absence, or duplication of the terminal CAA-CAG sequences (both encoding glutamine residues) in HTT, it was found that HD onset is best predicted by uninterrupted CAG repeat length and less well predicted by the polyQ repeat length.”

The new HD model is a bacterial artificial chromosome (BAC) transgenic mouse expressing full length human mutant huntingtin (mHTT) with about 120 uninterrupted CAG repeats. Gu stated, “Our new model is unique from a therapeutic perspective as it has the entire human huntingtin gene, including several DNA variants present in the patients, and it has a long and pure CAG repeat.” According to the authors, “… this new model exhibits additional key HD-like phenotypes that are mostly absent in the prior human genomic transgenic mouse models with numerous CAA interruptions in the DNA sequences encoding the mHTT polyQ stretch …” The new model demonstrates a subset of Huntington’s disease-like behavioral deficits, such as motor deficits and sleep disorders, and other characteristics that are largely absent in previous mouse models carrying the human huntingtin gene, such as pathological changes in non-neuronal cells and broad dysregulation of gene expression in the HD-vulnerable brain region.

Yang also noted, “In this study, we developed the first human genomic transgenic mouse model of Huntington’s disease with long—about 120—uninterrupted CAG repeats and compared the new model to our previous HD model with frequent CAA interruptions. Together, the studies showed that the long CAG repeat is selectively toxic to the striatum, the brain region that controls movement and cognition and is the most affected in Huntington’s disease.”

The authors concluded that the model demonstrates that long uninterrupted CAG repeats in human mHTT transgene can elicit multiple HD-like features that eluded previous human genomic transgenic mouse models, ” … including minimal body weight gain, somatic CAG repeat instability that is significantly correlated with behavioral deficits, striatum-selective and progressive NIs [nuclear inclusions] and transcriptional dysregulation, and striatal astrocytosis and microgliosis … Additionally, the BAC-CAG model represents the first human genomic transgenic mouse model with somatically unstable mHTT CAG repeats and the first HD animal model that shows significant correlations between somatic CAG repeat instability indices in the striatum or cortex and behavioral impairments.”

Yang also pointed out that among its findings, the study provided evidence that the new model with long CAG repeats may be toxic at the DNA, RNA, and protein levels in brain regions affected by Huntington’s around the time of disease onset.

The new model could be used to test candidate therapies to lower the human huntingtin and those targeting the toxicities originated from the pure CAG repeats in huntingtin, said Yang, adding that it also can be used to test combinatorial therapies against both types of targets. “The BAC-CAG mouse is the first and only HD mouse model that has both full-length human mHTT genomic transgene sequences (including some patient-associated SNPs) and shows mHTT CAG repeat instability,” the team noted. “Therefore, BAC-CAG is uniquely positioned to test the interactions of therapeutics that lower human HTT (or patient-associated mHTT allele) and those that target mHTT CAG repeat instability or other GWAS-associated DNA repair genes. Thus, the BAC-CAG mouse model may enable the advancement of polypharmacological therapies against multiple patient-derived therapeutic targets.”

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