DJ-1 Is a Redox-Dependent Molecular Chaperone That Inhibits α-Synuclein Aggregate Formation

Parkinson's disease (PD) pathology is characterized by the degeneration of midbrain dopamine neurons (DNs) ultimately leading to a progressive movement disorder in patients. The etiology of DN loss in sporadic PD is unknown, although it is hypothesized that aberrant protein aggregation and cellular oxidative stress may promote DN degeneration. Homozygous mutations in DJ-1 were recently described in two families with autosomal recessive inherited PD (Bonifati et al. 2003). In a companion article (Martinat et al. 2004), we show that mutations in DJ-1 alter the cellular response to oxidative stress and proteasomal inhibition. Here we show that DJ-1 functions as a redox-sensitive molecular chaperone that is activated in an oxidative cytoplasmic environment. We further demonstrate that DJ-1 chaperone activity in vivo extends to α-synuclein, a protein implicated in PD pathogenesis.帕金森病（Parkinson's disease, PD）的病理特征为中脑多巴胺能神经元（midbrain dopamine neurons, DNs）变性，最终导致患者出现进行性运动障碍。散发性PD中多巴胺能神经元丢失的病因尚未明确，尽管有假说提出异常蛋白质聚集与细胞氧化应激可能促进神经元变性。近期有研究在两个常染色体隐性遗传PD家系中报道了DJ-1基因的纯合突变（Bonifati等，2003）。在同期发表的姊妹篇研究论文（Martinat等，2004）中，本团队证实DJ-1突变会改变细胞对氧化应激与蛋白酶体抑制的应答反应。本研究证实，DJ-1可作为一种氧化还原敏感型分子伴侣，在氧化应激的胞质环境中被激活。本研究进一步证明，DJ-1在体内的分子伴侣活性可作用于α-突触核蛋白（α-synuclein）——一种与PD发病机制密切相关的蛋白质。