PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease
Summary: 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...
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Elsevier
2025-08-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725008022 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Claire Y. Chiang |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-3b0a69aa6c8a409f81f556359825f4ed |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-3b0a69aa6c8a409f81f556359825f4ed2025-08-20T02:40:32ZengElsevierCell Reports2211-12472025-08-0144811603110.1016/j.celrep.2025.116031PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s diseaseClaire Y. Chiang0Neringa Pratuseviciute1Yu-En Lin2Ayan Adhikari3Wondwossen M. Yeshaw4Chloe Flitton5Pemba L. Sherpa6Francesca Tonelli7Irena Rektorova8Timothy Lynch9Joanna Siuda10Monika Rudzińska-Bar11Oleksandr Pulyk12Peter Bauer13Christian Beetz14Dennis W. Dickson15Owen A. Ross16Zbigniew K. Wszolek17Zih-Hua Fang18Christine Klein19Alexander Zimprich20Dario R. Alessi21Esther M. Sammler22Suzanne R. Pfeffer23Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; Department of Neurology, Medical University of Vienna, Vienna, AustriaMRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UKDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USADepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USADepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USAAligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UKDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USAAligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UKSchool of Medicine and St Anne’s Hospital, 1st Department of Neurology, Pekarska 53, Brno, Czech RepublicDepartment of Neurology, Dublin Neurological Institute, Dublin, IrelandŚląski Uniwersytet Medyczny w Katowicach, Katowice, PolandDepartment of Neurology, Andrzej Frycz Modrzewski University, Krakow, PolandUzhhorod Regional Center of Neurosurgery & Neurology, Uzhhorod, UkraineCENTOGENE GmbH, Rostock, GermanyCENTOGENE GmbH, Rostock, GermanyMayo Clinic Florida, Department of Neuroscience, Jacksonville, FL 32224, USAMayo Clinic Florida, Department of Neuroscience, Jacksonville, FL 32224, USAMayo Clinic Florida, Department of Neuroscience, Jacksonville, FL 32224, USAGerman Center for Neurodegenerative Diseases, DZNE, Tübingen, GermanyInstitute of Neurogenetics, University of Lübeck, Lübeck, GermanyDepartment of Neurology, Medical University of Vienna, Vienna, AustriaAligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UKAligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UKDepartment of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124725008022CP: Cell biologyCP: Neuroscience |
| spellingShingle | 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 PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease Cell Reports CP: Cell biology CP: Neuroscience |
| title | PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease |
| title_full | PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease |
| title_fullStr | PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease |
| title_full_unstemmed | PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease |
| title_short | PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease |
| title_sort | ppm1m an lrrk2 counteracting phosphorab12 preferring phosphatase with a potential link to parkinson s disease |
| topic | CP: Cell biology CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725008022 |
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