PPM1M，一种与LRRK2相互作用、偏好磷酸化Rab12的磷酸酶，与帕金森病可能存在关联。

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

作者信息

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

机构信息

Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.

MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.

出版信息

Cell Rep. 2025 Aug 26;44(8):116031. doi: 10.1016/j.celrep.2025.116031. Epub 2025 Jul 20.

DOI:10.1016/j.celrep.2025.116031

PMID:40690364

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.

摘要

富含亮氨酸重复激酶2（LRRK2）可磷酸化一部分调节受体运输的Rab GTP酶，且LRRK2激活突变与帕金森病相关。Rab磷酸化是一个短暂事件，可被包括蛋白磷酸酶Mg2/Mn2依赖性1H（PPM1H）在内的磷酸酶逆转，PPM1H作用于磷酸化的Rab 8A（磷酸化Rab8A）和磷酸化Rab10。在此，我们报告了一项全磷酸酶组范围的小干扰RNA（siRNA）筛选，该筛选鉴定出PPM1M是一种优先作用于磷酸化Rab12的磷酸酶，它也作用于磷酸化Rab8A和磷酸化Rab10。从培养细胞或小鼠中敲除PPM1M后，其对磷酸化Rab12具有选择性。如先前在携带LRRK2通路突变的小鼠中所示，敲除Ppm1m会导致纹状体胆碱能和小白蛋白中间神经元中的初级纤毛丢失。我们还在帕金森病患者中鉴定出一种罕见的PPM1M突变，在体外和细胞中测试时该突变无催化活性。这些发现确定PPM1M是LRRK2信号通路中的关键因子，并为帕金森病患者可能的获益提供了一个新的治疗靶点。