title: LRRK2 affects vesicle trafficking, neurotransmitter extracellular level and membrane receptor localization.
abstract: 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 LRRK2(G2019S) 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 LRRK2(G2019S) shows an altered intracellular vesicle distribution. Taken together, our results point to the key role of LRRK2 to control vesicle trafficking in neuronal cells.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari, Sassari, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Migheli
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Del Giudice
authors.forename: Ylenia
authors.initials: Y
authors.lastname: Spissu
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sanna
authors.forename: Yulan
authors.initials: Y
authors.lastname: Xiong
authors.forename: Ted M
authors.initials: TM
authors.lastname: Dawson
authors.forename: Valina L
authors.initials: VL
authors.lastname: Dawson
authors.forename: Manuela
authors.initials: M
authors.lastname: Galioto
authors.forename: Gaia
authors.initials: G
authors.lastname: Rocchitta
authors.forename: Alice
authors.initials: A
authors.lastname: Biosa
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Serra
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Carri
authors.forename: Claudia
authors.initials: C
authors.lastname: Crosio
authors.forename: Ciro
authors.initials: C
authors.lastname: Iaccarino
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D017447:Receptors, Dopamine D1; C495280:LRRK2 protein, human; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine