title: LRRK2, a puzzling protein: insights into Parkinson's disease pathogenesis.
abstract: Leucine-rich repeat kinase 2 (LRRK2) is a large, ubiquitous protein of unknown function. Mutations in the gene encoding LRRK2 have been linked to familial and sporadic Parkinson's disease (PD) cases. The LRRK2 protein is a single polypeptide that displays GTPase and kinase activity. Kinase and GTPase domains are involved in different cellular signaling pathways. Despite several experimental studies associating LRRK2 protein with various intracellular membranes and vesicular structures such as endosomal/lysosomal compartments, the mitochondrial outer membrane, lipid rafts, microtubule-associated vesicles, the golgi complex, and the endoplasmic reticulum its broader physiologic function(s) remain unidentified. Additionally, the cellular distribution of LRRK2 may indicate its role in several different pathways, such as the ubiquitin-proteasome system, the autophagic-lysosomal pathway, intracellular trafficking, and mitochondrial dysfunction. This review discusses potential mechanisms through which LRRK2 may mediate neurodegeneration and cause PD.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal.
authors.forename: A Raquel
authors.initials: AR
authors.lastname: Esteves
authors.affiliation: University of Kansas Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal. Electronic address: cardoso.sandra.m@gmail.com.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
mesh_terms: D000818:Animals; D003599:Cytoskeleton / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011506:Proteins / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D011506:Proteins; D051844:alpha-Synuclein; C018589:lysosomal proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
keywords: Intracellular traffic; LRRK2; Mitochondria; Parkinson's disease; Quality control mechanisms