The homozygote VCP(R¹⁵⁵H/R¹⁵⁵H) mouse model exhibits accelerated human VCP-associated disease pathology.
The homozygote VCP(R¹⁵⁵H/R¹⁵⁵H) mouse model exhibits accelerated human VCP-associated disease pathology.
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DOI：
10.1371/journal.pone.0046308
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kimonis VE
中科院分区：
文献类型：
--
作者：
Nalbandian A;Llewellyn KJ;Kitazawa M;Yin HZ;Badadani M;Khanlou N;Edwards R;Nguyen C;Mukherjee J;Mozaffar T;Watts G;Weiss J;Kimonis VE
含瓦洛辛蛋白（Valosin containing protein，VCP）突变是遗传性包涵体肌病、佩吉特骨病、额颞叶痴呆（frontotemporal dementia，IBMPFD）的病因。VCP基因突变也与2%的孤立性家族性肌萎缩侧索硬化症（ALS）有关。VCP处于泛素蛋白酶体和自噬途径被破坏的交叉点，这些途径是负责细胞内蛋白质降解和在肌肉、脑和脊髓中观察到的异常病理的机制。我们已经开发了携带常见R155 H突变的纯合敲入VCP小鼠（VCPR 155 H/R155 H）模型，其发展了许多VCP相关人类疾病的典型临床特征。纯合子VCPR 155 H/R155 H小鼠通常存活不到21天，在EMG上表现出虚弱和肌病变化。骨骼的MicroCT成像显示近端胫骨和骨骼的不对称透亮线，高度提示PDB。VCPR 155 H/R155 H小鼠表现出显著的肌肉、心脏、脑和脊髓病理学，除了破坏的自噬和泛素病理学之外，还包括显著的线粒体异常。因此，VCPR 155 H/R155 H纯合小鼠代表了VCP疾病的加速模型，并可用于阐明VCP相关神经退行性疾病发病机制中涉及的复杂分子机制，并用于开发新的治疗策略。
Valosin containing protein (VCP) mutations are the cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD). VCP gene mutations have also been linked to 2% of isolated familial amyotrophic lateral sclerosis (ALS). VCP is at the intersection of disrupted ubiquitin proteasome and autophagy pathways, mechanisms responsible for the intracellular protein degradation and abnormal pathology seen in muscle, brain and spinal cord. We have developed the homozygous knock-in VCP mouse (VCPR155H/R155H) model carrying the common R155H mutations, which develops many clinical features typical of the VCP-associated human diseases. Homozygote VCPR155H/R155H mice typically survive less than 21 days, exhibit weakness and myopathic changes on EMG. MicroCT imaging of the bones reveal non-symmetrical radiolucencies of the proximal tibiae and bone, highly suggestive of PDB. The VCPR155H/R155H mice manifest prominent muscle, heart, brain and spinal cord pathology, including striking mitochondrial abnormalities, in addition to disrupted autophagy and ubiquitin pathologies. The VCPR155H/R155H homozygous mouse thus represents an accelerated model of VCP disease and can be utilized to elucidate the intricate molecular mechanisms involved in the pathogenesis of VCP-associated neurodegenerative diseases and for the development of novel therapeutic strategies.
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DOI：
10.1126/science.1201940
发表时间：
2011-08-26
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Green DR;Galluzzi L;Kroemer G
通讯作者：
Kroemer G
DOI：
10.1038/nsb972
发表时间：
2003-10-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
DeLaBarre, B;Brunger, AT
通讯作者：
Brunger, AT
影响因子：
9.9
作者：
Haubenberger, D;Bittner, RE;Zimprich, A
通讯作者：
Zimprich, A
影响因子：
4.2
作者：
Bersano, Anna;Del Bo, Roberto;Corti, Stefania
通讯作者：
Corti, Stefania
影响因子：
--
作者：
Fecto, Faisal;Yan, Jianhua;Siddique, Teepu
通讯作者：
Siddique, Teepu