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 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.