PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson’s disease
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<sup>+</sup>/Mn2<sup>+</sup> 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.
Authors
- Dennis W. Dickson (ORCID: https://orcid.org/0000-0001-7189-7917)
- Irena Rektorová (ORCID: https://orcid.org/0000-0002-5455-4573)
- Zih‐Hua Fang (ORCID: https://orcid.org/0000-0002-0225-8772)
- Christine Klein (ORCID: https://orcid.org/0000-0003-2102-3431)
- Alexander Zimprich (ORCID: https://orcid.org/0000-0002-1668-5177)
- Francesca Tonelli (ORCID: https://orcid.org/0000-0002-4600-6630)
- Suzanne R. Pfeffer (ORCID: https://orcid.org/0000-0002-6462-984X)
- Monika Rudzińska (ORCID: https://orcid.org/0000-0002-1453-6856)
- Yu‐En Lin (ORCID: https://orcid.org/0000-0002-5848-5405)
- Neringa Pratuseviciute (ORCID: https://orcid.org/0000-0002-1124-8699)
- Dario R. Alessi (ORCID: https://orcid.org/0000-0002-2140-9185)
- Joanna Siuda (ORCID: https://orcid.org/0000-0002-0340-660X)
- O. R. Pulyk (ORCID: https://orcid.org/0000-0002-8717-047X)
- Ayan Adhikari (ORCID: https://orcid.org/0000-0002-8525-3263)
- Esther Sammler (ORCID: https://orcid.org/0000-0003-3218-7116)
- Wondwossen M Yeshaw (ORCID: https://orcid.org/0000-0002-3134-3458)
- Owen A. Ross (ORCID: https://orcid.org/0000-0003-4813-756X)
- Claire Y Chiang (ORCID: https://orcid.org/0000-0002-0999-9856)
- Peter Bauer (ORCID: https://orcid.org/0000-0001-9414-4555)
- Christian Beetz (ORCID: https://orcid.org/0000-0001-7061-2895)
- Zbigniew K. Wszolek
- Timothy Lynch (ORCID: https://orcid.org/0000-0002-2380-8737)
- Chloe Flitton (ORCID: https://orcid.org/0009-0005-2778-8381)
- Pemba Sherpa (ORCID: https://orcid.org/0000-0002-4678-0001)
Institutions
- University of Dundee (GB)
- University of Economics in Katowice (PL)
- German Center for Neurodegenerative Diseases (DE)
- Jacksonville College (US)
- Górnośląskie Centrum Medyczne (PL)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- St. Anne's University Hospital Brno (CZ)
- Centogene (Germany) (DE)
- Mayo Clinic in Florida (US)
- Andrzej Frycz Modrzewski Krakow University (PL)
- Collegium Medicum in Bydgoszcz (PL)
- Medical University of Vienna (AT)
- Uzhhorod National University (UA)
- University of Lübeck (DE)
- Stanford University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-07-20
- DOI
- https://doi.org/10.1016/j.celrep.2025.116031
- Citations
- 3
- Primary Topic
- Protein Kinase Regulation and GTPase Signaling
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Aligning Science Across Parkinson’s
- National Institutes of Health
- National Institute of General Medical Sciences