PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with 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+/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.