Hijioka Masanori, Inden Masatoshi, Yanagisawa Daijiro, Kitamura Yoshihisa
Laboratory of Pharmacology and Neurobiology, College of Pharmaceutical Sciences, Ritsumeikan University.
Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University.
Biol Pharm Bull. 2017;40(5):548-552. doi: 10.1248/bpb.b16-01006.
DJ-1, encoded in a causative gene of familial Parkinson's disease (PARK7), has multiple functions: it works as an antioxidant, in transcriptional regulation, as a molecular chaperone and in protein degradation. Three types of pathogenic mutants of DJ-1 (M26I, D149A and L166P) have been reported to disrupt proper structures and lead to a loss of function. DJ-1 receives oxidation at the cysteine residue, and the degree of oxidation at the C106 residue determines DJ-1 activity. In this decade, DJ-1 has been reported to suppress the progression of various neurodegenerative disorders in animal models. The administration of recombinant wild-type DJ-1 protein suppresses the neuronal loss associated with both Parkinson's disease and ischemic stroke in rats. Furthermore, in studies focused on DJ-1 as the therapeutic target, compounds that have the capacity of binding to DJ-1 at the C106 residue have been reported to exert therapeutic effects on various neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and ischemic stroke. DJ-1 and DJ-1-targeting molecules/compounds will be useful therapeutic targets for various neurodegenerative disorders due to their various functions such as antioxidant capacity, chaperone function and as a proteolytic pathway.
DJ-1由家族性帕金森病（PARK7）的致病基因编码，具有多种功能：作为抗氧化剂、参与转录调控、作为分子伴侣以及参与蛋白质降解。据报道，DJ-1的三种致病突变体（M26I、D149A和L166P）会破坏其正常结构并导致功能丧失。DJ-1在半胱氨酸残基处发生氧化，C106残基的氧化程度决定了DJ-1的活性。在这十年间，据报道DJ-1在动物模型中可抑制各种神经退行性疾病的进展。给予重组野生型DJ-1蛋白可抑制大鼠帕金森病和缺血性中风相关的神经元损失。此外，在将DJ-1作为治疗靶点的研究中，据报道能够与C106残基处的DJ-1结合的化合物对帕金森病、阿尔茨海默病和缺血性中风等各种神经退行性疾病具有治疗作用。由于DJ-1及其靶向分子/化合物具有抗氧化能力、伴侣功能和蛋白水解途径等多种功能，它们将成为各种神经退行性疾病有用的治疗靶点。
