TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS.
TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS.
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Torsina在ALS的秀丽隐杆线虫模型中挽救了与ER相关的应力和机车缺陷。
DOI：
10.1242/dmm.013615
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发表时间：
2014-02
影响因子：
4.3
通讯作者：
Caldwell GA
中科院分区：
文献类型：
--
作者：
Thompson ML;Chen P;Yan X;Kim H;Borom AR;Roberts NB;Caldwell KA;Caldwell GA
神经退行性疾病的分子机制聚集在影响细胞应激、蛋白质稳态和衰老的途径的界面上。靶向神经保护蛋白的内在能力来恢复神经元功能和/或减轻变性是一种潜在的治疗干预手段。人类DYT1基因的产物torsinA是功能多样的AAA+蛋白家族的一员，在体外和体内都表现出强大的分子伴侣样活性。尽管DYT1突变与一种罕见的遗传性全身性肌张力障碍有关，但torsinA的天然功能似乎在维持内质网（ER）应激的细胞阈值方面具有细胞保护作用。在这里，我们探索了torsinA作为缓冲物的潜力，以减轻与神经退行性疾病肌萎缩性侧索硬化症（ALS）有关的错误折叠蛋白应激的细胞后果。在含有超氧化物歧化酶（SOD1）突变的ALS小鼠模型中，运动神经元对变性的选择性易感性已被发现与大脑区域特异性内质网应激相关。我们利用秀丽隐杆线虫作为模拟内质网应激的系统，制备了过表达野生型或突变型人类SOD1的转基因线虫，以评估它们在体内对内质网应激诱导的相对影响。这些研究揭示了突变sod1特异性内质网应激的增加，温度的变化进一步加剧了内质网应激，所有这些都被torsinA的共表达强有力地减弱了。此外，通过互补行为分析，torsinA能够恢复突变G85R SOD1动物的正常神经元功能。此外，torsinA通过蛋白酶体靶向突变体SOD1进行降解，这代表了torsinA对易聚集蛋白活性的机制见解。这些结果扩大了我们对影响ALS神经元功能障碍的蛋白抑制机制的理解，同时强调了torsinA作为治疗开发新靶点的潜力。
Molecular mechanisms underlying neurodegenerative diseases converge at the interface of pathways impacting cellular stress, protein homeostasis and aging. Targeting the intrinsic capacities of neuroprotective proteins to restore neuronal function and/or attenuate degeneration represents a potential means toward therapeutic intervention. The product of the human DYT1 gene, torsinA, is a member of the functionally diverse AAA+ family of proteins and exhibits robust molecular-chaperone-like activity, both in vitro and in vivo. Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress. Here we explore the potential for torsinA to serve as a buffer to attenuate the cellular consequences of misfolded-protein stress as it pertains to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The selective vulnerability of motor neurons to degeneration in ALS mouse models harboring mutations in superoxide dismutase (SOD1) has been found to correlate with regional-specific ER stress in brains. Using Caenorhabditis elegans as a system to model ER stress, we generated transgenic nematodes overexpressing either wild-type or mutant human SOD1 to evaluate their relative impact on ER stress induction in vivo. These studies revealed a mutant-SOD1-specific increase in ER stress that was further exacerbated by changes in temperature, all of which was robustly attenuated by co-expression of torsinA. Moreover, through complementary behavioral analysis, torsinA was able to restore normal neuronal function in mutant G85R SOD1 animals. Furthermore, torsinA targeted mutant SOD1 for degradation via the proteasome, representing mechanistic insight on the activity that torsinA has on aggregate-prone proteins. These results expand our understanding of proteostatic mechanisms influencing neuronal dysfunction in ALS, while simultaneously highlighting the potential for torsinA as a novel target for therapeutic development.
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DOI：
10.1042/bss0670151
发表时间：
2001-01-01
期刊：
NEURONAL SIGNAL TRANSDUCTION AND ALZHEIMER'S DISEASE
影响因子：
--
作者：
Mattson, MP;Gary, DS;Duan, WZ
通讯作者：
Duan, WZ
DOI：
10.1073/pnas.0304375101
发表时间：
2004-01-20
影响因子：
11.1
作者：
Goodchild, RE;Dauer, WT
通讯作者：
Dauer, WT
影响因子：
4.8
作者：
Atkin, Julie D.;Farg, Manal A.;Horne, Malcolm K.
通讯作者：
Horne, Malcolm K.
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D
建立新型线虫模型以研究自噬在肌萎缩侧索硬化症中的作用
影响因子：
8.2
作者：
Li, Jia;Huang, Kai-xing;Le, Wei-dong
通讯作者：
Le, Wei-dong