Abstract

DJ-1, also known as Parkinson’s disease protein 7, is a multifunctional protein ubiquitously expressed in cells and tissues. Interacting with proteins of various intracellular compartments, DJ-1 plays an important role in maintaining different cellular functions. Mutant DJ-1 forms containing amino acid substitutions (especially L166P), typical of Parkinson’s disease, are characterized by impaired dimerization, stability, and folding. DJ-1 exhibits several types of catalytic activity; however, in the enzyme classification it exists as protein deglycase (EC 3.5.1.124). Apparently, in different cell compartments DJ-1 exhibits catalytic and non-catalytic functions, and their ratio still remains unknown. Oxidative stress promotes dissociation of cytoplasmic DJ-1 dimers into monomers, which are translocated to the nucleus, where this protein acts as a coactivator of various signaling pathways, preventing cell death. In mitochondria, DJ-1 is found in the synthasome, where it interacts with the β ATP synthase subunit. Downregulation of the DJ-1 gene under conditions of experimental PD increases sensitivity of the cells to neurotoxins, and introduction of the recombinant DJ-1 protein attenuates manifestation of this pathology. The thirteen-membered fragment of the DJ-1 amino acid sequence attached to the heptapeptide of the TAT protein penetrating into the cells exhibited neuroprotective properties in various PD models both in cell cultures and after administration to animals. Low molecular weight DJ-1 ligands also demonstrate therapeutic potential, providing neuroprotective effects seen during their incubation with cells and administration to animals.

中文翻译：

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DJ-1蛋白及其在帕金森氏病发展中的作用：实验模型的研究

摘要

DJ-1，也称为帕金森氏病蛋白7，是一种在细胞和组织中普遍表达的多功能蛋白。与各种细胞内区室的蛋白质相互作用，DJ-1在维持不同的细胞功能中起着重要的作用。帕金森氏病典型的含有氨基酸取代（特别是L166P）的突变DJ-1形式的特征是二聚化，稳定性和折叠能力受损。DJ-1表现出几种类型的催化活性。但是，在酶分类中，它以蛋白质脱糖酶的形式存在（EC 3.5.1.124）。显然，在不同的细胞室中，DJ-1表现出催化和非催化功能，其比例仍然未知。氧化应激促进细胞质DJ-1二聚体解离为单体，这些单体易位至细胞核，该蛋白可充当各种信号通路的共激活因子，从而防止细胞死亡。在线粒体中，DJ-1存在于合酶体中，并与βATP合酶亚基相互作用。下调在实验性PD的条件下DJ-1基因增加了细胞对神经毒素的敏感性，重组DJ-1蛋白的引入减弱了这种病理表现。与TAT蛋白的七肽连接的DJ-1氨基酸序列的13元片段穿透细胞进入细胞，在各种PD模型中，无论是在细胞培养中还是施用于动物后，都表现出神经保护特性。低分子量DJ-1配体也具有治疗潜力，可在与细胞孵育并施用于动物时提供神经保护作用。