An automated and quantitative method to evaluate progression of striatal pathology in Huntington's disease transgenic...

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSN). A number of genetic mouse models have been developed to model HD phenotype. Most of these models display impaired performance in motor coordination assays and variety of neuropathological abnormalities. Quantitative neuropathological assessment in these mice requires application of stereological techniques and very labor-intensive and time consuming. Here, we report a development of a novel paradigm that simplifies and accelerates quantitative evaluation of striatal atrophy in HD mice. To achieve this goal, we crossed YAC128 HD transgenic mice with Rgs9-EGFP mice. In Rgs9-EGFP mice the EGFP transgene is expressed selectively in MSN neurons at high levels. Using high resolution fluorescence laser scanning imager, we have been able to precisely measure striatal area and intensity of EGFP expression in coronal slices from these mice at 2 months, 4 months and 9 months of age. Using this approach, we demonstrated significant reduction in striatal volume in YAC128 mice at 4 months and 9 months of age when compared to wild type littermates. We evaluated behavior performance of these mice at 2 months, 4 months and 6 months of age and demonstrated significant impairment of YAC128 mice in beam walk assay at 4 months and 6 months of age. This new mouse model and the quantitative neuropathological scoring paradigm may simplify and accelerate discovery of novel neuroprotective agents for HD.