TY  - JOUR
AU  - Chiang, Claire Y
AU  - Pratuseviciute, Neringa
AU  - Lin, Yu-En
AU  - Adhikari, Ayan
AU  - Yeshaw, Wondwossen M
AU  - Flitton, Chloe
AU  - Sherpa, Pemba L
AU  - Tonelli, Francesca
AU  - Rektorova, Irena
AU  - Lynch, Timothy
AU  - Siuda, Joanna
AU  - Rudzińska-Bar, Monika
AU  - Pulyk, Oleksandr
AU  - Bauer, Peter
AU  - Beetz, Christian
AU  - Dickson, Dennis W
AU  - Ross, Owen A
AU  - Wszolek, Zbigniew K
AU  - Fang, Zih-Hua
AU  - Klein, Christine
AU  - Zimprich, Alexander
AU  - Alessi, Dario R
AU  - Sammler, Esther M
AU  - Pfeffer, Suzanne R
TI  - PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.
JO  - Cell reports
VL  - 44
IS  - 8
SN  - 2211-1247
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - DZNE-2025-00998
SP  - 116031 -
PY  - 2025
AB  - 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.
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: pathology
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
KW  - Animals
KW  - Humans
KW  - Mice
KW  - rab GTP-Binding Proteins: metabolism
KW  - Phosphorylation
KW  - HEK293 Cells
KW  - Protein Phosphatase 2C: metabolism
KW  - Protein Phosphatase 2C: genetics
KW  - Mutation
KW  - Mice, Knockout
KW  - CP: Cell biology (Other)
KW  - CP: Neuroscience (Other)
KW  - LRRK2 kinase (Other)
KW  - Parkinson’s disease (Other)
KW  - Rab GTPase (Other)
KW  - phosphatase (Other)
KW  - primary cilia (Other)
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
KW  - rab GTP-Binding Proteins (NLM Chemicals)
KW  - Protein Phosphatase 2C (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40690364
DO  - DOI:10.1016/j.celrep.2025.116031
UR  - https://pub.dzne.de/record/280915
ER  -