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

TY - JOUR

T1 - PPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease

AU - Global Parkinson's Genetics Program (GP2)

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.

N1 - Publisher Copyright: © 2025 The Author(s)

PY - 2025/8/26

Y1 - 2025/8/26

N2 - 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.

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 - CP: Cell biology

KW - CP: Neuroscience

KW - LRRK2 kinase

KW - Parkinson's disease

KW - phosphatase

KW - primary cilia

KW - Rab GTPase

UR - https://www.scopus.com/pages/publications/105010970001

U2 - 10.1016/j.celrep.2025.116031

DO - 10.1016/j.celrep.2025.116031

M3 - Article

C2 - 40690364

AN - SCOPUS:105010970001

SN - 2639-1856

VL - 44

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 116031

ER -