Department of Biochemistry, Stanford University School of Medicine, Stanford, United States.
MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
Elife. 2018 Nov 6;7:e40202. doi: 10.7554/eLife.40202.
Parkinson's disease-associated LRRK2 kinase phosphorylates multiple Rab GTPases, including Rab8A and Rab10. We show here that LRRK2 kinase interferes with primary cilia formation in cultured cells, human LRRK2 G2019S iPS cells and in the cortex of LRRK2 R1441C mice. Rab10 phosphorylation strengthens its intrinsic ability to block ciliogenesis by enhancing binding to RILPL1. Importantly, the ability of LRRK2 to interfere with ciliogenesis requires both Rab10 and RILPL1 proteins. Pathogenic LRRK2 influences the ability of cells to respond to cilia-dependent, Hedgehog signaling as monitored by Gli1 transcriptional activation. Moreover, cholinergic neurons in the striatum of LRRK2 R1441C mice show decreased ciliation, which will decrease their ability to sense Sonic hedgehog in a neuro-protective circuit that supports dopaminergic neurons. These data reveal a molecular pathway for regulating cilia function that likely contributes to Parkinson's disease-specific pathology.
This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).
帕金森病相关的 LRRK2 激酶磷酸化多种 Rab GTPases，包括 Rab8A 和 Rab10。我们在这里显示，LRRK2 激酶干扰培养细胞、人类 LRRK2 G2019S iPS 细胞和 LRRK2 R1441C 小鼠皮质中的初级纤毛形成。Rab10 磷酸化通过增强与 RILPL1 的结合，增强其阻止纤毛发生的固有能力。重要的是，LRRK2 干扰纤毛发生的能力需要 Rab10 和 RILPL1 蛋白。致病性 LRRK2 通过影响细胞响应依赖纤毛的 Hedgehog 信号的能力来发挥作用，这可以通过 Gli1 转录激活来监测。此外，LRRK2 R1441C 小鼠纹状体中的胆碱能神经元表现出纤毛减少，这将降低它们在支持多巴胺能神经元的神经保护回路中感知 Sonic hedgehog 的能力。这些数据揭示了一种调节纤毛功能的分子途径，可能导致帕金森病特有的病理学。
本文经过编辑过程，作者决定如何处理同行评审期间提出的问题。审稿人的评估是所有问题都已得到解决（见评审意见）。
