A novel and accurate full-length HTT mouse model for Huntington’s disease

Here, we report the generation and characterization of a novel Huntington’s disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full-length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like psychiatric and cognitive phenotypes at 2 months. From 3 to 4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibited neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions, and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers, and testing gene-targeting therapeutic approaches for HD.

Download Full-text

A novel and accurate full-length HTT mouse model for Huntington's disease

10.1101/2021.06.14.448318 ◽

2021 ◽

Author(s):

Chenjian Li ◽

Sushuang Zheng ◽

Sushila A Shenoy ◽

Wencheng Liu ◽

Yuanyi Dai ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Artificial Chromosome ◽

Regulatory Elements ◽

Full Length ◽

Motor Deficits ◽

The Novel ◽

Full Spectrum ◽

Age Dependent

Here we report the generation and characterization of a novel Huntington's disease (HD) mouse model BAC226Q by using a bacterial artificial chromosome (BAC) system, expressing full length human HTT with ~226 CAG-CAA repeats and containing endogenous human HTT promoter and regulatory elements. BAC226Q recapitulated a full-spectrum of age-dependent and progressive HD-like phenotypes without unwanted and erroneous phenotypes. BAC226Q mice developed normally, and gradually exhibited HD-like mood and cognitive phenotypes at 2 months. From 3-4 months, BAC226Q mice showed robust progressive motor deficits. At 11 months, BAC226Q mice showed significant reduced life span, gradual weight loss and exhibit neuropathology including significant brain atrophy specific to striatum and cortex, striatal neuronal death, widespread huntingtin inclusions and reactive pathology. Therefore, the novel BAC226Q mouse accurately recapitulating robust, age-dependent, progressive HD-like phenotypes will be a valuable tool for studying disease mechanisms, identifying biomarkers and testing gene-targeting therapeutic approaches for HD.

Download Full-text

Faculty Opinions recommendation of Wheel running from a juvenile age delays onset of specific motor deficits but does not alter protein aggregate density in a mouse model of Huntington's disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1106030.562154 ◽

2008 ◽

Author(s):

Allan Tobin

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Wheel Running ◽

Motor Deficits ◽

Protein Aggregate ◽

Juvenile Age

Download Full-text

Age-dependent alterations in the cortical entrainment of subthalamic nucleus neurons in the YAC128 mouse model of Huntington's disease

Neurobiology of Disease ◽

10.1016/j.nbd.2015.03.006 ◽

2015 ◽

Vol 78 ◽

pp. 88-99 ◽

Cited By ~ 6

Author(s):

Joshua W. Callahan ◽

Elizabeth D. Abercrombie

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Subthalamic Nucleus ◽

Age Dependent ◽

Yac128 Mouse ◽

Cortical Entrainment

Download Full-text

Abnormalities in the Motor Unit of a Fast-Twitch Lower Limb Skeletal Muscle in Huntington’s Disease

ASN NEURO ◽

10.1177/1759091419886212 ◽

2019 ◽

Vol 11 ◽

pp. 175909141988621 ◽

Cited By ~ 2

Author(s):

Priscila Aparecida Costa Valadão ◽

Bárbara Campos de Aragão ◽

Jéssica Neves Andrade ◽

Matheus Proença S. Magalhães-Gomes ◽

Giselle Foureaux ◽

...

Keyword(s):

Mouse Model ◽

Huntington's Disease ◽

Huntington’S Disease ◽

Tibialis Anterior ◽

Neuromuscular Junctions ◽

Motor Behavior ◽

Psychiatric Symptoms ◽

Artificial Chromosome ◽

Ultrastructural Level ◽

Fast Twitch

Huntington’s disease (HD) is a disorder characterized by chronic involuntary movements, dementia, and psychiatric symptoms. It is caused by a mutation in the gene that encodes for huntingtin protein (HTT), leading to the formation of mutant proteins expressed in various tissues. Although brain pathology has become the hallmark for HD, recent studies suggest that damage of peripheral structures also contributes to HD progression. We previously identified severe alterations in the motor units that innervate cervical muscles in 12-month-old BACHD (Bacterial Artificial Chromosome Huntington’s Disease) mice, a well-established mouse model for HD. Here, we studied lumbar motoneurons and their projections onto hind limb fast-twitch skeletal muscles (tibialis anterior), which control balance and gait in HD patients. We found that lumbar motoneurons were altered in the HD mouse model; the number and size of lumbar motoneurons were reduced in BACHD. Structural alterations were also present in the sciatic nerve and neuromuscular junctions. Acetylcholine receptors were organized in several small patches (acetylcholine receptor fragmentation), many of which were partially innervated. In BACHD mice, we observed atrophy of tibialis anterior muscles, decreased expression of glycolytic fast Type IIB fibers, and at the ultrastructural level, alterations of sarcomeres and mitochondria. Corroborating all these findings, BACHD animals performed worse on motor behavior tests. Our results provide additional evidences that nerve–muscle communication is impaired in HD and that motoneurons from distinct spinal cord locations are similarly affected in the disease.

Download Full-text