PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2025-07-20 DOI:10.1016/j.celrep.2025.116031

Claire Y Chiang, Neringa Pratuseviciute, Yu-En Lin, Ayan Adhikari, Wondwossen M Yeshaw, Chloe Flitton, Pemba L Sherpa, Francesca Tonelli, Irena Rektorova, Timothy Lynch, Joanna Siuda, Monika Rudzińska-Bar, Oleksandr Pulyk, Peter Bauer, Christian Beetz, Dennis W Dickson, Owen A Ross, Zbigniew K Wszolek, Zih-Hua Fang, Christine Klein, Alexander Zimprich, Dario R Alessi, Esther M Sammler, Suzanne R Pfeffer

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引用次数: 0

Abstract

Leucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking, and LRRK2-activating mutations are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including protein phosphatase, Mg2⁺/Mn2⁺ dependent 1H (PPM1H), which acts on phosphorylated Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a phosphatome-wide small interfering RNA (siRNA) screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cultured cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic and parvalbumin interneurons. We also identified a rare PPM1M mutation in patients with Parkinson's disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson's disease.

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PPM1M，一种对抗lrrk2、偏好磷酸化ab12的磷酸酶，与帕金森病有潜在联系。

富亮氨酸重复激酶2 （LRRK2）磷酸化调节受体运输的Rab gtpase亚群，LRRK2激活突变与帕金森病有关。Rab磷酸化是一个短暂的事件，可以被磷酸酶逆转，包括蛋白磷酸酶，Mg2+/Mn2+依赖1H (PPM1H)，它作用于磷酸化的Rab8A （phospab8a）和phospab10。在这里，我们报告了一个磷酸化小干扰RNA （siRNA）筛选，发现PPM1M是一个磷酸化ab12偏好磷酸酶，也作用于磷酸化ab8a和磷酸化ab10。从培养细胞或小鼠中敲除后，PPM1M对phospab12表现出选择性。如先前在LRRK2通路突变小鼠中所示，敲除Ppm1m会导致纹状体胆碱能和小白蛋白中间神经元的初级纤毛丢失。我们还在帕金森病患者中发现了一种罕见的PPM1M突变，该突变在体外和细胞中均无催化活性。这些发现确定PPM1M是LRRK2信号通路的关键参与者，并为帕金森病患者的可能获益提供了新的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.