title: Identification of protein phosphatase 2A as an interacting protein of leucine-rich repeat kinase 2.
abstract: Mutations in the gene coding for the multi-domain protein leucine-rich repeat kinase 2 (LRRK2) are the leading cause of genetically inherited Parkinson's disease (PD). Two of the common found mutations are the R1441C and G2019S. In this study we identified protein phosphatase 2A (PP2A) as an interacting partner of LRRK2. We were able to demonstrate that the Ras of complex protein (ROC) domain is sufficient to interact with the three subunits of PP2A in human neuroblastoma SH-SY5Y cells and in HeLa cells. The alpha subunit of PP2A is interacting with LRRK2 in the perinuclear region of HeLa cells. Silencing the catalytic subunit of PP2A by shRNA aggravated cellular degeneration induced by the pathogenic R1441C-LRRK2 mutant expressed in neuroblastoma SH-SY5Y cells. A similar enhancement of apoptotic nuclei was observed by downregulation of the catalytic subunit of PP2A in cultured cortical cells derived from neurons overexpressing the pathogenic mutant G2019S-LRRK2. Conversely, pharmacological activation of PP2A by sodium selenate showed a partial neuroprotection from R1441C-LRRK2-induced cellular degeneration. All these data suggest that PP2A is a new interacting partner of LRRK2 and reveal the importance of PP2A as a potential therapeutic target in PD.
authors.forename: Panagiotis S
authors.initials: PS
authors.lastname: Athanasopoulos
authors.forename: Wright
authors.initials: W
authors.lastname: Jacob
authors.forename: Sebastian
authors.initials: S
authors.lastname: Neumann
authors.forename: Miriam
authors.initials: M
authors.lastname: Kutsch
authors.forename: Dirk
authors.initials: D
authors.lastname: Wolters
authors.forename: Eng K
authors.initials: EK
authors.lastname: Tan
authors.forename: Zoë
authors.initials: Z
authors.lastname: Bichler
authors.forename: Christian
authors.initials: C
authors.lastname: Herrmann
authors.forename: Rolf
authors.initials: R
authors.lastname: Heumann
mesh_terms: D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011485:Protein Binding; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D064586:Selenic Acid / Q000494:pharmacology
chemical_list: D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D054648:Protein Phosphatase 2; D064586:Selenic Acid