Liang Xia, Wu Jun, Egorova Polina, Bezprozvanny Ilya
Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.
Laboratory of Molecular Neurodegeneration (LMN), St Petersburg State Polytechnical University, St Petersburg, Russia.
J Huntingtons Dis. 2014;3(4):343-350. doi: 10.3233/JHD-140128.
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.
亨廷顿舞蹈症（HD）是一种进行性神经退行性疾病，由亨廷顿蛋白中的多聚谷氨酰胺扩增引起，导致纹状体中等棘状神经元（MSN）选择性退化。已经开发了许多基因小鼠模型来模拟HD表型。这些模型中的大多数在运动协调试验中表现受损，并伴有各种神经病理学异常。对这些小鼠进行定量神经病理学评估需要应用体视学技术，且非常耗费人力和时间。在此，我们报告了一种新的范例的开发，该范例简化并加速了对HD小鼠纹状体萎缩的定量评估。为实现这一目标，我们将YAC128 HD转基因小鼠与Rgs9-EGFP小鼠进行杂交。在Rgs9-EGFP小鼠中，EGFP转基因在MSN神经元中高水平选择性表达。使用高分辨率荧光激光扫描成像仪，我们能够精确测量这些小鼠在2个月、4个月和9个月大时冠状切片中纹状体面积和EGFP表达强度。使用这种方法，我们证明与野生型同窝小鼠相比，YAC128小鼠在4个月和9个月大时纹状体体积显著减小。我们评估了这些小鼠在2个月、4个月和6个月大时的行为表现，证明YAC128小鼠在4个月和6个月大时在横梁行走试验中存在显著损伤。这种新的小鼠模型和定量神经病理学评分范例可能会简化并加速针对HD的新型神经保护剂的发现。
