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首页> 外文期刊>eLife journal >A pathway for Parkinson’s Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain
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A pathway for Parkinson’s Disease LRRK2 kinase to block primary cilia and Sonic hedgehog signaling in the brain

机译：帕金森氏病LRRK2激酶阻断大脑中初级纤毛和声波刺猬信号的途径

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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.
机译：帕金森氏病相关的LRRK2激酶使包括Rab8A和Rab10在内的多个Rab GTPases磷酸化。我们在这里显示LRRK2激酶会干扰培养的细胞，人LRRK2 G2019S iPS细胞和LRRK2 R1441C小鼠皮层中的初级纤毛形成。 Rab10磷酸化通过增强与RILPL1的结合来增强其阻断纤毛发生的内在能力。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影响细胞响应纤毛依赖性刺猬信号的能力，如Gli1转录激活所监测的。此外，LRRK2 R1441C小鼠纹状体中的胆碱能神经元显示纤毛减少，这将降低它们在支持多巴胺能神经元的神经保护电路中感知音速刺猬的能力。这些数据揭示了调节纤毛功能的分子途径，这可能有助于帕金森氏病的特定病理。

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