• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>PLoS Genetics >Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16
【2h】

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16

机译：CHIP的结构破坏和异常功能介导了SCAR16临床前模型中运动和认知功能的丧失

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.
机译：鉴于CHIP具有同时充当伴侣蛋白和泛素连接酶的功能，人们一直认为CHIP（与热休克70相互作用的蛋白的羧基末端）是细胞蛋白质质量控​​制系统的活跃成员。我们发现了一种遗传疾病，现在称为脊髓小脑常染色体隐性遗传病16（SCAR16），是由导致CHIP泛素连接酶功能丧失的编码突变引起的。描述SCAR16的最初突变是CHIP的泛素连接酶结构域中的错义突变（p.T246M）。使用多种生物物理和细胞方法，我们证明了T246M突变会导致CHIP U-box结构域的结构紊乱和错误折叠，促进寡聚化，并增加蛋白酶体依赖性转换。 CHIP-T246M没有连接酶活性，但与伴侣和伴侣相关功能保持相互作用。为了建立SCAR16的临床前模型，我们在小鼠和大鼠的内源性基因座上设计了T246M。 T246M纯合子的动物的认知和运动性小脑功能障碍与在CHIP无效动物模型中观察到的不同，并且在学习和记忆方面也有所欠缺，这反映了SCAR16患者的认知障碍。我们得出的结论是，T246M突变并不等同于CHIP的全部丧失，这支持了以下概念：致病的CHIP突变对CHIP的功能具有不同的生物物理和功能影响，可能与SCAR16患者中观察到的临床表型谱直接相关。我们的发现不仅进一步扩展了我们对CHIP生物学的基本理解，而且为SCAR16疾病病理学的分子驱动因素提供了有意义的机制见解，可用于为这种毁灭性疾病的新型治疗方法提供信息。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号