Journal Article

DZNE-2025-00998

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.

Chiang, C. Y. ; Pratuseviciute, N. ; Lin, Y.-E. ; Adhikari, A. ; Yeshaw, W. M. ; Flitton, C. ; Sherpa, P. L. ; Tonelli, F. ; Rektorova, I. ; Lynch, T. ; Siuda, J. ; Rudzińska-Bar, M. ; Pulyk, O. ; Bauer, P. ; Beetz, C. ; Dickson, D. W. ; Ross, O. A. ; Wszolek, Z. K. ; Program, G. P. G. (Collaboration Author) ; Fang, Z.-H.DZNE* ; Klein, C. ; Zimprich, A. ; Alessi, D. R. ; Sammler, E. M. ; Pfeffer, S. R.

2025
Cell Press Maryland Heights, MO

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Please use a persistent id in citations: doi:10.1016/j.celrep.2025.116031

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.

Keyword(s): Parkinson Disease: metabolism (MeSH) ; Parkinson Disease: genetics (MeSH) ; Parkinson Disease: pathology (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism (MeSH) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; rab GTP-Binding Proteins: metabolism (MeSH) ; Phosphorylation (MeSH) ; HEK293 Cells (MeSH) ; Protein Phosphatase 2C: metabolism (MeSH) ; Protein Phosphatase 2C: genetics (MeSH) ; Mutation (MeSH) ; Mice, Knockout (MeSH) ; CP: Cell biology ; CP: Neuroscience ; LRRK2 kinase ; Parkinson’s disease ; Rab GTPase ; phosphatase ; primary cilia ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; rab GTP-Binding Proteins ; Protein Phosphatase 2C

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Contributing Institute(s):

1. Genome Biology of Neurodegenerative Diseases (AG Heutink)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)

Appears in the scientific report 2025

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