Minami Akari, Nakanishi Atsuko, Matsuda Satoru, Kitagishi Yasuko, Ogura Yasunori
Department of Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan.
Int J Mol Med. 2015 Jan;35(1):3-9. doi: 10.3892/ijmm.2014.1980. Epub 2014 Oct 27.
α-Synuclein (α-syn) is the major protein component of Lewy bodies, a key pathological characteristic of the degenerating brain. The misfolding and aggregation of α-syn is associated with both the idiopathic and familial forms of Parkinson's disease (PD) and Lewy body dementia (LBD). However, the function of α-syn is poorly understood, as it shows both neurotoxic and neuroprotective activities. Mutations in phosphatase and tensin homologue-induced putative kinase 1 (PINK1) also cause recessively inherited PD. Studies support the notion of neuroprotective roles for PINK1, as it protects cells from damage-induced mitochondrial dysfunction, oxidative stress and cell apoptosis. PINK1 plays an essential role in mitochondrial quality control and its homeostasis is maintained through mitochondrial stabilization. The α-syn aggregation is linked to various aspects of mitochondrial dysfunction and PINK1-related mitophagy. Determination of the molecular pathways that lead to α-syn oligomerization and further aggregation may be the basis for the successful design and development of treatments for these neurodegenerative diseases. The present review summarizes the function of PINK1 underlying α-syn aggregation and the mechanisms through which mitochondrial dysfunction plays a role in this process.
α-突触核蛋白（α-syn）是路易小体的主要蛋白质成分，而路易小体是大脑退化的一个关键病理特征。α-突触核蛋白的错误折叠和聚集与特发性和家族性帕金森病（PD）以及路易体痴呆（LBD）均有关联。然而，α-突触核蛋白的功能却鲜为人知，因为它既表现出神经毒性，又具有神经保护活性。磷酸酶和张力蛋白同源物诱导的假定激酶1（PINK1）的突变也会导致隐性遗传的帕金森病。研究支持PINK1具有神经保护作用这一观点，因为它能保护细胞免受损伤诱导的线粒体功能障碍、氧化应激和细胞凋亡的影响。PINK1在线粒体质量控制中起着至关重要的作用，其稳态通过线粒体稳定得以维持。α-突触核蛋白的聚集与线粒体功能障碍和PINK1相关的线粒体自噬的各个方面都有关联。确定导致α-突触核蛋白寡聚化并进一步聚集的分子途径，可能是成功设计和开发这些神经退行性疾病治疗方法的基础。本综述总结了PINK1在α-突触核蛋白聚集过程中的作用以及线粒体功能障碍在这一过程中发挥作用的机制。
