Animal Models of Huntington's Disease

Huntington’s Disease Overview

The progressive loss of structure or function of brain neurons causes a variety of neurological diseases, which are collectively referred to as neurodegenerative diseases, and Huntington's disease. Huntington's disease, also known as Huntington's chorea, is a kind of autosomal dominant neurodegenerative disease characterized by motor disorders, mental disorders, and progressive dementia. Mutation (expansion of trinucleotide repeats of CAG) in the gene encoding the huntingtin protein produces mutated huntingtin that gradually gathers in striatal neurons to form large molecular clusters. These clusters are toxic, accumulating in the neurons and affecting the function of nerves and the brain. More and more parts of the brain, such as the hypothalamus and cortex, are affected as the disease progresses, and the symptoms gradually worsen, eventually leading to death.

Animal Models of Huntington’s Disease

Animal models have made huge contributions to pathogenetic pathway investigations and new therapy discoveries of human diseases, especially to these neurological disorders. Lots of attempts have been made in animal modeling to mimic different aspects of human Huntington’s disease, which covers a wide range of animal species such as fruit flies, rodents, sheep, even pigs, and non-human primates. All these animal models are divided into genetic and non-genetic models based on the alterations in animal genes.

Earlier research before the publication of huntingtin mutation pathogenesis, the establishment of Huntington’s disease models is mainly modeled by neurotoxin-mediated striatal lesioning. Since the striatum is the main neurodegenerative site of Huntington’s disease, glutamate receptor agonists (e.g., quinolinic acid, kainic acid) and mitochondrial toxins (e.g., 3-nitropropionic acid, malonic acid) are used to induce striatum injury in rodents and non-human primates. These models can be established in several days, which are useful to clarify the potential pathogenetic pathways and processes.

The discovery of huntingtin mutation in 1993 prompted the development of genetic animal models of human Huntington’s disease, including transgenic models and knock-in models. A variety of Huntington’s disease genetic animal models have been reported, which is mainly include but not limited to:

• R6/2 transgenic mouse: the most used mouse model by inserting exon 1 of human HTT gene into the mouse, expressing 144 CAG repeats.
• R6/1 transgenic mouse: like R6/2 transgenic mouse but expressing 116 CAG repeats.
• HN171-82Q transgenic mouse: modeling by inserting the first 171 amino acids at the N-terminal of the human HTT gene into the mouse, expressing 82 CAG repeats.
• YAC/BAC transgenic mouse: the full-length mutant HTT transgenic mice established by yeast artificial chromosome (YAC) technology and bacterial artificial chromosome (BAC) technology, expressing 128 or 72 CAG repeats, respectively.
• HdhQ92, HdhQ111, CAG140, or CAG15O knock-in mouse: human HTT gene is partially or full-length knocked in the mouse, making the mouse carry CAG tract-expanded HTT gene and expressing CAG repeats.
• Other Transgenic animal models: transgenic Caenorhabditis elegans models, transgenic Drosophila melanogaster models, transgenic sheep, Tibetan miniature pig, and rhesus macaque.

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