Langston Rebekah G, Rudenko Iakov N, Cookson Mark R
Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD 20892, U.S.A.
Biochem J. 2016 Feb 1;473(3):221-32. doi: 10.1042/BJ20150985.
In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.
自富亮氨酸重复激酶2（LRRK2）被确定为晚发性常染色体显性帕金森病的致病基因以来，大量工作致力于了解LRRK2蛋白是否可能成为帕金森病（PD）的可药物作用靶点。作为这项工作的一部分，已开发出动物模型来探索LRRK2的正常功能和病理生理作用。然而，LRRK2是一个更广泛的蛋白质家族的成员，其在不同生物体中的功能仍知之甚少。在这篇综述中，我们比较了从无脊椎动物（如秀丽隐杆线虫和黑腹果蝇）到哺乳动物等不同物种的LRRK2同源物和直系同源物的生化特性信息。我们特别讨论了哺乳动物LRRK2同源物LRRK1，以及那些只有单一LRRK同源物的物种，探讨了LRRK蛋白家族中每个成员具有不同特性的例子以及那些似乎存在功能冗余的情况。我们得出结论，揭示LRRK2直系同源物的功能将有助于阐明人类LRRK2的关键特性，以及增进对不同动物模型用于研究LRRK2相关帕金森病适用性的理解。
