人类含 valosin 蛋白病的进展性翻译小鼠模型：VCP（R155H/+）小鼠。
A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse.
机构信息
Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA.
出版信息
Muscle Nerve. 2013 Feb;47(2):260-70. doi: 10.1002/mus.23522. Epub 2012 Nov 21.
INTRODUCTION
Mutations in the valosin-containing protein (VCP) gene cause hereditary inclusion body myopathy (IBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently, these mutations have been linked to 2% of familial amyotrophic lateral sclerosis (ALS) cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis.
METHODS
The VCP(R155H/+) knock-in mouse model was assessed for muscle strength and immunohistochemical, Western blot, apoptosis, autophagy, and microPET/CT imaging analyses.
RESULTS
VCP(R155H/+) mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies, and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons.
CONCLUSIONS
VCP(R155H/+) knock-in mice represent an excellent preclinical model for understanding VCP-associated disease mechanisms and future treatments.
简介
包含缬氨酸蛋白（VCP）基因的突变导致与 Pagets 骨病（PDB）和额颞叶痴呆（FTD）相关的遗传性包涵体肌病（IBM）。最近，这些突变与 2%的家族性肌萎缩侧索硬化症（ALS）病例有关。敲入小鼠模型为研究 VCP 相关发病机制提供了机会。
方法
评估 VCP（R155H/+）敲入小鼠模型的肌肉力量以及免疫组织化学、Western blot、细胞凋亡、自噬和 microPET/CT 成像分析。
结果
VCP（R155H/+）小鼠出现显著的进行性肌肉无力，股四头肌和大脑出现进行性细胞质 TDP-43、泛素阳性包涵体和 LC3-II 染色增加。微 CT 分析显示长骨末端出现 Pagets 样病变。脊髓显示运动神经元的神经退行性变化、泛素和 TDP-43 病理学。
结论
VCP（R155H/+）敲入小鼠是一种极好的临床前模型，可用于了解 VCP 相关疾病机制和未来的治疗方法。
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