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

Area of Science:

• Neuroscience
• Genetics
• Animal Models

Background:

• Huntington's disease (HD) is a progressive neurodegenerative disorder.
• Existing mouse models often lack full-spectrum recapitulation of HD phenotypes.
• Development of accurate models is crucial for therapeutic research.

Purpose of the Study:

• To generate and characterize a novel bacterial artificial chromosome (BAC) based mouse model for Huntington's disease.
• To assess the model's ability to recapitulate key HD-like phenotypes and neuropathology.

Main Methods:

• Generation of the BAC226Q mouse model expressing full-length human HTT with expanded CAG-CAA repeats using a BAC system.
• Comprehensive characterization of behavioral, cognitive, motor, and neuropathological phenotypes in BAC226Q mice.
• Longitudinal assessment of disease progression, including lifespan, weight, brain atrophy, neuronal death, and huntingtin inclusions.

Main Results:

• The BAC226Q model exhibited normal development and progressively displayed HD-like psychiatric and cognitive deficits starting at 2 months.
• Robust motor deficits were observed between 3-4 months.
• At 11 months, mice showed reduced lifespan, weight loss, brain atrophy (striatum and cortex), striatal neuronal death, huntingtin inclusions, and reactive pathology.

Conclusions:

• The BAC226Q mouse model accurately recapitulates a full spectrum of age-dependent and progressive HD-like phenotypes and neuropathology.
• This model serves as a valuable tool for investigating HD pathogenesis.
• BAC226Q mice are suitable for biomarker discovery and evaluating gene-targeting therapeutic strategies for Huntington's disease.