Lee Chiao-Yin, Menozzi Elisa, Chau Kai-Yin, Schapira Anthony H V
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, Maryland, USA.
J Neurochem. 2021 Dec;159(5):826-839. doi: 10.1111/jnc.15524. Epub 2021 Oct 16.
The glucocerebrosidase 1 gene (GBA1), bi-allelic variants of which cause Gaucher disease (GD), encodes the lysosomal enzyme glucocerebrosidase (GCase) and is a risk factor for Parkinson Disease (PD). GBA1 variants are linked to a reduction in GCase activity in the brain. Variants in Leucine-Rich Repeat Kinase 2 (LRRK2), such as the gain-of-kinase-function variant G2019S, cause the most common familial form of PD. In patients without GBA1 and LRRK2 mutations, GCase and LRRK2 activity are also altered, suggesting that these two genes are implicated in all forms of PD and that they may play a broader role in PD pathogenesis. In this review, we review the proposed roles of GBA1 and LRRK2 in PD, focussing on the endolysosomal pathway. In particular, we highlight the discovery of Ras-related in brain (Rab) guanosine triphosphatases (GTPases) as LRRK2 kinase substrates and explore the links between increased LRRK2 activity and Rab protein function, lysosomal dysfunction, alpha-synuclein accumulation and GCase activity. We also discuss the discovery of RAB10 as a potential mediator of LRRK2 and GBA1 interaction in PD. Finally, we discuss the therapeutic implications of these findings, including current approaches and future perspectives related to novel drugs targeting LRRK2 and GBA1.
葡萄糖脑苷脂酶1基因（GBA1）的双等位基因变异会导致戈谢病（GD），该基因编码溶酶体酶葡萄糖脑苷脂酶（GCase），并且是帕金森病（PD）的一个风险因素。GBA1变异与大脑中GCase活性降低有关。富含亮氨酸重复激酶2（LRRK2）的变异，如激酶功能获得性变异G2019S，会导致最常见的家族性帕金森病形式。在没有GBA1和LRRK2突变的患者中，GCase和LRRK2的活性也会发生改变，这表明这两个基因与所有形式的帕金森病都有关，并且它们可能在帕金森病发病机制中发挥更广泛的作用。在这篇综述中，我们回顾了GBA1和LRRK2在帕金森病中所提出的作用重点关注内溶酶体途径。特别是，我们强调了作为LRRK2激酶底物的脑内Ras相关鸟苷三磷酸酶（Rab GTP酶）的发现，并探讨了LRRK2活性增加与Rab蛋白功能、溶酶体功能障碍、α-突触核蛋白积累和GCase活性之间的联系。我们还讨论了RAB10作为帕金森病中LRRK2和GBA1相互作用的潜在介质的发现。最后，我们讨论了这些发现的治疗意义，包括目前的方法以及与靶向LRRK2和GBA1的新型药物相关的未来前景。
