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000280915 0247_ $$2doi$$a10.1016/j.celrep.2025.116031
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000280915 037__ $$aDZNE-2025-00998
000280915 041__ $$aEnglish
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000280915 1001_ $$aChiang, Claire Y$$b0
000280915 245__ $$aPPM1M, an LRRK2-counteracting, phosphoRab12-preferring phosphatase with a potential link to Parkinson's disease.
000280915 260__ $$aMaryland Heights, MO$$bCell Press$$c2025
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000280915 520__ $$aLeucine-rich repeat kinase 2 (LRRK2) phosphorylates a subset of Rab GTPases that regulate receptor trafficking, and LRRK2-activating mutations are linked to Parkinson's disease. Rab phosphorylation is a transient event that can be reversed by phosphatases, including protein phosphatase, Mg2+/Mn2+ dependent 1H (PPM1H), which acts on phosphorylated Rab 8A (phosphoRab8A) and phosphoRab10. Here, we report a phosphatome-wide small interfering RNA (siRNA) screen that identified PPM1M as a phosphoRab12-preferring phosphatase that also acts on phosphoRab8A and phosphoRab10. Upon knockout from cultured cells or mice, PPM1M displays selectivity for phosphoRab12. As shown previously for mice harboring LRRK2 pathway mutations, knockout of Ppm1m leads to primary cilia loss in striatal cholinergic and parvalbumin interneurons. We also identified a rare PPM1M mutation in patients with Parkinson's disease that is catalytically inactive when tested in vitro and in cells. These findings identify PPM1M as a key player in the LRRK2 signaling pathway and provide a new therapeutic target for the possible benefit of patients with Parkinson's disease.
000280915 536__ $$0G:(DE-HGF)POF4-354$$a354 - Disease Prevention and Healthy Aging (POF4-354)$$cPOF4-354$$fPOF IV$$x0
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000280915 650_7 $$2Other$$aCP: Cell biology
000280915 650_7 $$2Other$$aCP: Neuroscience
000280915 650_7 $$2Other$$aLRRK2 kinase
000280915 650_7 $$2Other$$aParkinson’s disease
000280915 650_7 $$2Other$$aRab GTPase
000280915 650_7 $$2Other$$aphosphatase
000280915 650_7 $$2Other$$aprimary cilia
000280915 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000280915 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$arab GTP-Binding Proteins
000280915 650_7 $$0EC 3.1.3.16$$2NLM Chemicals$$aProtein Phosphatase 2C
000280915 650_2 $$2MeSH$$aParkinson Disease: metabolism
000280915 650_2 $$2MeSH$$aParkinson Disease: genetics
000280915 650_2 $$2MeSH$$aParkinson Disease: pathology
000280915 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
000280915 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000280915 650_2 $$2MeSH$$aAnimals
000280915 650_2 $$2MeSH$$aHumans
000280915 650_2 $$2MeSH$$aMice
000280915 650_2 $$2MeSH$$arab GTP-Binding Proteins: metabolism
000280915 650_2 $$2MeSH$$aPhosphorylation
000280915 650_2 $$2MeSH$$aHEK293 Cells
000280915 650_2 $$2MeSH$$aProtein Phosphatase 2C: metabolism
000280915 650_2 $$2MeSH$$aProtein Phosphatase 2C: genetics
000280915 650_2 $$2MeSH$$aMutation
000280915 650_2 $$2MeSH$$aMice, Knockout
000280915 7001_ $$aPratuseviciute, Neringa$$b1
000280915 7001_ $$aLin, Yu-En$$b2
000280915 7001_ $$aAdhikari, Ayan$$b3
000280915 7001_ $$aYeshaw, Wondwossen M$$b4
000280915 7001_ $$aFlitton, Chloe$$b5
000280915 7001_ $$aSherpa, Pemba L$$b6
000280915 7001_ $$aTonelli, Francesca$$b7
000280915 7001_ $$aRektorova, Irena$$b8
000280915 7001_ $$aLynch, Timothy$$b9
000280915 7001_ $$aSiuda, Joanna$$b10
000280915 7001_ $$aRudzińska-Bar, Monika$$b11
000280915 7001_ $$aPulyk, Oleksandr$$b12
000280915 7001_ $$aBauer, Peter$$b13
000280915 7001_ $$aBeetz, Christian$$b14
000280915 7001_ $$aDickson, Dennis W$$b15
000280915 7001_ $$aRoss, Owen A$$b16
000280915 7001_ $$aWszolek, Zbigniew K$$b17
000280915 7001_ $$aProgram, Global Parkinson’s Genetics$$b18$$eCollaboration Author
000280915 7001_ $$0P:(DE-2719)9001362$$aFang, Zih-Hua$$b19$$udzne
000280915 7001_ $$aKlein, Christine$$b20
000280915 7001_ $$aZimprich, Alexander$$b21
000280915 7001_ $$aAlessi, Dario R$$b22
000280915 7001_ $$aSammler, Esther M$$b23
000280915 7001_ $$aPfeffer, Suzanne R$$b24
000280915 773__ $$0PERI:(DE-600)2649101-1$$a10.1016/j.celrep.2025.116031$$gVol. 44, no. 8, p. 116031 -$$n8$$p116031 -$$tCell reports$$v44$$x2211-1247$$y2025
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