Araki Miho, Ito Genta, Tomita Taisuke
Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Laboratory of Brain and Neurological Disorders, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Neuronal Signal. 2018 Oct 10;2(4):NS20180005. doi: 10.1042/NS20180005. eCollection 2018 Dec.
Leucine-rich repeat kinase 2 (LRRK2) encodes a 2527-amino acid (aa) protein composed of multiple functional domains, including a Ras of complex proteins (ROC)-type GTP-binding domain, a carboxyl terminal of ROC (COR) domain, a serine/threonine protein kinase domain, and several repeat domains. LRRK2 is genetically involved in the pathogenesis of both sporadic and familial Parkinson's disease (FPD). Parkinson's disease (PD) is the second most common neurodegenerative disorder, manifesting progressive motor dysfunction. PD is pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, and the presence of intracellular inclusion bodies called Lewy bodies (LB) in the remaining neurons. As the most frequent PD-causing mutation in LRRK2, G2019S, increases the kinase activity of LRRK2, an abnormal increase in LRRK2 kinase activity is believed to contribute to PD pathology; however, the precise biological functions of LRRK2 involved in PD pathogenesis remain unknown. Although biochemical studies have discovered several substrate proteins of LRRK2 including Rab GTPases and tau, little is known about whether excess phosphorylation of these substrates is the cause of the neurodegeneration in PD. In this review, we summarize latest findings regarding the physiological and pathological functions of LRRK2, and discuss the possible molecular mechanisms of neurodegeneration caused by LRRK2 and its substrates.
富含亮氨酸重复激酶2（LRRK2）编码一种由2527个氨基酸组成的蛋白质，该蛋白质由多个功能域构成，包括一个复杂蛋白质的Ras（ROC）型GTP结合域、一个ROC羧基末端（COR）域、一个丝氨酸/苏氨酸蛋白激酶域以及几个重复域。LRRK2在散发性和家族性帕金森病（FPD）的发病机制中均有遗传方面的关联。帕金森病（PD）是第二常见的神经退行性疾病，表现为进行性运动功能障碍。PD的病理特征是黑质致密部多巴胺能神经元的丧失，以及在其余神经元中存在称为路易小体（LB）的细胞内包涵体。作为LRRK2中最常见的导致PD的突变，G2019S增加了LRRK2的激酶活性，据信LRRK2激酶活性的异常增加促成了PD病理；然而，LRRK2在PD发病机制中的确切生物学功能仍不清楚。尽管生化研究已经发现了LRRK2的几种底物蛋白，包括Rab GTP酶和tau，但对于这些底物的过度磷酸化是否是PD神经退行性变的原因知之甚少。在这篇综述中，我们总结了关于LRRK2生理和病理功能的最新发现，并讨论了由LRRK2及其底物引起神经退行性变的可能分子机制。
