LRRK2 Affects Vesicle Trafficking, Neurotransmitter Extracellular Level and Membrane Receptor Localization

The leucine-rich repeat kinase 2 (LRRK2) gene was found to play a role in the pathogenesis of both familial and sporadic Parkinson’s disease (PD). LRRK2 encodes a large multi-domain protein that is expressed in different tissues. To date, the physiological and pathological functions of LRRK2 are not clearly defined. In this study we have explored the role of LRRK2 in controlling vesicle trafficking in different cellular or animal models and using various readouts. In neuronal cells, the presence of LRRK2G2019S pathological mutant determines increased extracellular dopamine levels either under basal conditions or upon nicotine stimulation. Moreover, mutant LRRK2 affects the levels of dopamine receptor D1 on the membrane surface in neuronal cells or animal models. Ultrastructural analysis of PC12-derived cells expressing mutant LRRK2G2019S shows an altered intracellular vesicle distribution. Taken together, our results point to the key role of LRRK2 to control vesicle trafficking in neuronal cells.

[1]  C. Crosio,et al.  LRRK2 and vesicle trafficking. , 2012, Biochemical Society transactions.

[2]  P. Verstreken,et al.  LRRK2 Controls an EndoA Phosphorylation Cycle in Synaptic Endocytosis , 2012, Neuron.

[3]  T. Dawson,et al.  ArfGAP1 Is a GTPase Activating Protein for LRRK2: Reciprocal Regulation of ArfGAP1 by LRRK2 , 2012, The Journal of Neuroscience.

[4]  F. Obata,et al.  LRRK2 Phosphorylates Tubulin-Associated Tau but Not the Free Molecule: LRRK2-Mediated Regulation of the Tau-Tubulin Association and Neurite Outgrowth , 2012, PloS one.

[5]  H. Cai,et al.  Loss of leucine-rich repeat kinase 2 causes age-dependent bi-phasic alterations of the autophagy pathway , 2012, Molecular Neurodegeneration.

[6]  P. Verstreken,et al.  Synaptic vesicle trafficking and Parkinson's disease , 2012, Developmental neurobiology.

[7]  Wei Lu,et al.  The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease , 2011, Nature Immunology.

[8]  N. Hattori,et al.  [Etiology and pathogenesis of Parkinson's disease: from mitochondrial dysfunctions to familial Parkinson's disease]. , 2004, Rinsho shinkeigaku = Clinical neurology.

[9]  C. Crosio,et al.  Bcl2-A1 interacts with pro-caspase-3: Implications for amyotrophic lateral sclerosis , 2011, Neurobiology of Disease.

[10]  A. Bonci,et al.  Endocytosis Promotes Rapid Dopaminergic Signaling , 2011, Neuron.

[11]  W. Hong,et al.  Temporal Expression of Mutant LRRK2 in Adult Rats Impairs Dopamine Reuptake , 2011, International journal of biological sciences.

[12]  Y. Liu,et al.  Dopaminergic Neuronal Loss, Reduced Neurite Complexity and Autophagic Abnormalities in Transgenic Mice Expressing G2019S Mutant LRRK2 , 2011, PloS one.

[13]  W. Wurst,et al.  LRRK2 Controls Synaptic Vesicle Storage and Mobilization within the Recycling Pool , 2011, The Journal of Neuroscience.

[14]  David I. Bass,et al.  Impaired dopaminergic neurotransmission and microtubule-associated protein tau alterations in human LRRK2 transgenic mice , 2010, Neurobiology of Disease.

[15]  Kwang-Soo Kim,et al.  Coordinate Regulation of Neurite Outgrowth by LRRK2 and Its Interactor, Rab5 , 2010, Experimental neurobiology.

[16]  N. Sokol,et al.  Pathogenic LRRK2 negatively regulates microRNA-mediated translational repression , 2010, Nature.

[17]  J. Buxbaum,et al.  Enhanced Striatal Dopamine Transmission and Motor Performance with LRRK2 Overexpression in Mice Is Eliminated by Familial Parkinson's Disease Mutation G2019S , 2010, The Journal of Neuroscience.

[18]  H. Cai,et al.  Phosphorylation of Ezrin/Radixin/Moesin Proteins by LRRK2 Promotes the Rearrangement of Actin Cytoskeleton in Neuronal Morphogenesis , 2009, The Journal of Neuroscience.

[19]  F. Gillardon.  Leucine‐rich repeat kinase 2 phosphorylates brain tubulin‐beta isoforms and modulates microtubule stability – a point of convergence in Parkinsonian neurodegeneration? , 2009, Journal of neurochemistry.

[20]  R. Burke,et al.  Mutant LRRK2R1441G BAC transgenic mice recapitulate cardinal features of Parkinson's disease , 2009, Nature Neuroscience.

[21]  M. Cookson,et al.  Leucine-rich repeat kinase 2 mutations and Parkinson’s disease: three questions , 2009, ASN neuro.

[22]  L. Pei,et al.  Extracellular dopamine induces the oxidative toxicity of SH‐SY5Y cells , 2008, Synapse.

[23]  R. Takahashi,et al.  Phosphorylation of 4E‐BP by LRRK2 affects the maintenance of dopaminergic neurons in Drosophila , 2008, The EMBO journal.

[24]  J. Lowry,et al.  Novel integrated microdialysis-amperometric system for in vitro detection of dopamine secreted from PC12 cells: design, construction, and validation. , 2008, Analytical biochemistry.

[25]  Saskia Biskup,et al.  Genes associated with Parkinson syndrome , 2008, Journal of Neurology.

[26]  I. Marín,et al.  The Roco protein family: a functional perspective , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  E. Tolosa,et al.  Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study , 2008, The Lancet Neurology.

[28]  N. Hattori,et al.  LRRK2 regulates synaptic vesicle endocytosis. , 2008, Experimental cell research.

[29]  Sul-Hee Chung,et al.  Overexpression of APP stimulates basal and constitutive exocytosis in PC12 cells , 2008, Neuroscience Letters.

[30]  P. Barone,et al.  Apoptotic mechanisms in mutant LRRK2-mediated cell death. , 2007, Human molecular genetics.

[31]  N. Hattori,et al.  Leucine-rich repeat kinase 2 associates with lipid rafts. , 2007, Human molecular genetics.

[32]  P. Emson,et al.  Localization of LRRK2 to membranous and vesicular structures in mammalian brain , 2006, Annals of neurology.

[33]  C. Ross,et al.  Kinase activity of mutant LRRK2 mediates neuronal toxicity , 2006, Nature Neuroscience.

[34]  V. Bonifati.  The pleomorphic pathology of inherited parkinson’s disease: Lessons from LRRK2 , 2006, Current neurology and neuroscience reports.

[35]  David W. Miller,et al.  Kinase activity is required for the toxic effects of mutant LRRK2/dardarin , 2006, Neurobiology of Disease.

[36]  Daniel Choquet,et al.  AMPA and NMDA glutamate receptor trafficking: multiple roads for reaching and leaving the synapse , 2006, Cell and Tissue Research.

[37]  C. Ross,et al.  Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[38]  A. Leenders,et al.  Differential signaling in presynaptic neurotransmitter release , 2005, Cellular and Molecular Life Sciences CMLS.

[39]  Thomas Meitinger,et al.  Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology , 2004, Neuron.

[40]  Andrew Lees,et al.  Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease , 2004, Neuron.

[41]  Silvio O Rizzoli,et al.  The Structural Organization of the Readily Releasable Pool of Synaptic Vesicles , 2004, Science.

[42]  M. Mura,et al.  Role of the nitric oxide/cyclic GMP pathway and ascorbic acid in 3-morpholinosydnonimine (SIN-1)-induced increases in dopamine secretion from PC12 cells. A microdialysis in vitro study , 2003, Neuroscience Letters.

[43]  M. Mura,et al.  Role of the nitric oxide/cyclic GMP pathway and extracellular environment in the nitric oxide donor‐induced increase in dopamine secretion from PC12 cells: a microdialysis in vitro study , 2003, Journal of neurochemistry.

[44]  H. Melikian,et al.  Regulation of neuronal function by protein trafficking: a role for the endosomal pathway , 2000, The Journal of physiology.

[45]  K. Vrana,et al.  Dopamine toxicity in neuroblastoma cells: role of glutathione depletion by l-BSO and apoptosis , 2000, Brain Research.

[46]  L. Sciola,et al.  Enhancing Effect of Manganese on L‐DOPA‐Induced Apoptosis in PC12 Cells , 1999, Journal of neurochemistry.

[47]  M. Uhler,et al.  Transient transfection studies of secretion in bovine chromaffin cells and PC12 cells. Generation of kainate-sensitive chromaffin cells. , 1993, The Journal of biological chemistry.

[48]  R. Roth,et al.  In vitro microdialysis: a novel technique for stimulated neurotransmitter release measurements , 1991, Journal of Neuroscience Methods.

[49]  P. Lazarovici,et al.  Regulation of the differentiation of PC12 pheochromocytoma cells. , 1989, Environmental health perspectives.

[50]  M. Youdim,et al.  Selective mao a and b inhibitors: Their mechanism of action and pharmacology , 1983, Neuropharmacology.

[51]  S. U. Kim,et al.  Isolation and characterization of chromaffin granules from a pheochromocytoma (PC 12) cell line. , 1980, Experimental cell research.

[52]  W. Betz,et al.  Synaptic vesicle pools , 2005, Nature Reviews Neuroscience.

[53]  T. Martin,et al.  PC12 cells as a model for studies of regulated secretion in neuronal and endocrine cells. , 2003, Methods in cell biology.

[54]  S. R. Nash,et al.  Dopamine receptors: from structure to function. , 1998, Physiological reviews.

[55]  L. Shenkman,et al.  Purification and characterization of tyrosine hydroxylase from a clonal pheochromocytoma cell line. , 1980, Molecular pharmacology.