title: Synphilin-1 attenuates mutant LRRK2-induced neurodegeneration in Parkinson's disease models.
abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) cause autosomal-dominant Parkinsonism with pleomorphic pathology including deposits of aggregated protein and neuronal degeneration. The pathogenesis of LRRK2-linked Parkinson's disease (PD) is not fully understood. Here, using co-immunoprecipitation, we found that LRRK2 interacted with synphilin-1 (SP1), a cytoplasmic protein that interacts with α-synuclein and has implications in PD pathogenesis. LRRK2 interacted with the N-terminus of SP1 whereas SP1 predominantly interacted with the C-terminus of LRRK2, including kinase domain. Co-expression of SP1 with LRRK2 increased LRRK2-induced cytoplasmic aggregation in cultured cells. Moreover, SP1 also attenuated mutant LRRK2-induced toxicity and reduced LRRK2 kinase activity in cultured cells. Knockdown of SP1 by siRNA enhanced LRRK2 neuronal toxicity. In vivo Drosophila studies, co-expression of SP1 and mutant G2019S-LRRK2 in double transgenic Drosophila increased survival and improved locomotor activity. Expression of SP1 protects against G2019S-LRRK2-induced dopamine neuron loss and reduced LRRK2 phosphorylation in double transgenic fly brains. Our findings demonstrate that SP1 attenuates mutant LRRK2-induced PD-like phenotypes and plays a neural protective role.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Jingnan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Thomas
authors.affiliation: Division of Neurobiology, Department of Psychiatry.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Pei
authors.affiliation: Division of Neurobiology, Department of Psychiatry.
authors.forename: Haibing
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, The B. Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Simone
authors.initials: S
authors.lastname: Engelender
authors.affiliation: Division of Neurobiology, Department of Psychiatry, Departments of Neuroscience, Neurology, and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA and wsmith@rx.umaryland.edu caross@jhu.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA, wsmith@rx.umaryland.edu caross@jhu.edu.
authors.forename: Wanli W
authors.initials: WW
authors.lastname: Smith
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004330:Drosophila; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C118958:SNCAIP protein, human; D051844:alpha-Synuclein; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D004298:Dopamine