Brehme Marc, Voisine Cindy, Rolland Thomas, Wachi Shinichiro, Soper James H, Zhu Yitan, Orton Kai, Villella Adriana, Garza Dan, Vidal Marc, Ge Hui, Morimoto Richard I
Proteostasis Therapeutics, Inc., Cambridge, MA 02139, USA; Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
Cell Rep. 2014 Nov 6;9(3):1135-50. doi: 10.1016/j.celrep.2014.09.042. Epub 2014 Oct 23.
Chaperones are central to the proteostasis network (PN) and safeguard the proteome from misfolding, aggregation, and proteotoxicity. We categorized the human chaperome of 332 genes into network communities using function, localization, interactome, and expression data sets. During human brain aging, expression of 32% of the chaperome, corresponding to ATP-dependent chaperone machines, is repressed, whereas 19.5%, corresponding to ATP-independent chaperones and co-chaperones, are induced. These repression and induction clusters are enhanced in the brains of those with Alzheimer's, Huntington's, or Parkinson's disease. Functional properties of the chaperome were assessed by perturbation in C. elegans and human cell models expressing Aβ, polyglutamine, and Huntingtin. Of 219 C. elegans orthologs, knockdown of 16 enhanced both Aβ and polyQ-associated toxicity. These correspond to 28 human orthologs, of which 52% and 41% are repressed, respectively, in brain aging and disease and 37.5% affected Huntingtin aggregation in human cells. These results identify a critical chaperome subnetwork that functions in aging and disease.
伴侣蛋白是蛋白质稳态网络（PN）的核心，可保护蛋白质组免于错误折叠、聚集和蛋白毒性。我们利用功能、定位、相互作用组和表达数据集，将由332个基因组成的人类伴侣蛋白组分类为网络群落。在人类大脑衰老过程中，占伴侣蛋白组32%的与ATP依赖型伴侣蛋白机器相对应的基因表达受到抑制，而占19.5%的与ATP非依赖型伴侣蛋白和共伴侣蛋白相对应的基因表达则被诱导。在患有阿尔茨海默病、亨廷顿舞蹈病或帕金森病的人的大脑中，这些抑制和诱导簇会增强。通过在表达Aβ、多聚谷氨酰胺和亨廷顿蛋白的秀丽隐杆线虫和人类细胞模型中进行干扰，评估了伴侣蛋白组的功能特性。在219个秀丽隐杆线虫直系同源物中，敲低16个会增强Aβ和多聚谷氨酰胺相关的毒性。这些对应于28个人类直系同源物，其中52%和41%分别在大脑衰老和疾病中受到抑制，37.5%影响人类细胞中的亨廷顿蛋白聚集。这些结果确定了一个在衰老和疾病中起作用的关键伴侣蛋白子网。
