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FLASH GENE
Symbol LRRK2 contributors: mct/shn - updated : 05-10-2013
HGNC name leucine-rich repeat kinase 2
HGNC id 18618
Corresponding disease
PARK8 Parkinson disease 8
Location 12q12      Physical location : 40.618.812 - 40.763.084
Synonym name
  • Parkinson disease (autosomal dominant)
  • augmented in rheumatoid arthritis 17
  • leucine-rich repeat serine/threonine-protein kinase 2
  • Synonym symbol(s) ROCO2, FLJ45829, RIPK7, DKFZp434H2111, AURA17, DARDARIN, PARK8
    EC.number 2.7.11.1
    DNA
    TYPE functioning gene
    STRUCTURE 144.27 kb     51 Exon(s)
    MAPPING cloned Y linked N status provisional
    Map cen - D12S331 - LRRK2 - D12S1668 - D12S1589 - tel
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    51 - 9239 280 2527 - - 16269541
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrinethyroid   highly
    Lymphoid/Immunethymus   highly Homo sapiens
    Nervousbrainbasal nucleiputamen  
     brainmidbrainsubstantia nigra   Homo sapiens
     brainbasal nucleistriatum highly Homo sapiens
     brainforebraincerebral cortex highly Homo sapiens
     brainlimbic systemhippocampus   Homo sapiens
    Urinarykidneytubule    Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Nervousneuron
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a leucine-rich repeat (LRR) domain
  • a DFG-like motif
  • a RAS domain
  • a central catalytic core region containing a GTP-binding Ras of complex protein (Roc) domain,
  • a C-terminal of ROC (COR) domain and a kinase domain
  • a MLK-like domain
  • a WD40 domain
  • conjugated PhosphoP
    mono polymer dimer
    HOMOLOGY
    interspecies ortholog to LRRK2, Pan troglodytes
    ortholog to Lrrk2, Rattus norvegicus
    ortholog to Lrrk2, Mus musculus
    ortholog to lrrk2, Danio rerio
    Homologene
    FAMILY
  • leucine-rich repeat kinase family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria,outer
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,cytosolic,vesicle
    text
  • localized in synaptic vesicles
  • normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with Lewy bodies diseases
  • locate to membrane microdomains such as the neck of caveolae, microvilli/filopodia and intraluminal vesicles of multivesicular bodies
  • basic FUNCTION
  • serine/threonine kinase capable of activating the MAPK pathway in multiple cell lines in a kinase-independent fashion
  • potentiating neurotoxicity in a kinase-dependent manner (critical component of biochemical activity linking LRRK2 with neurodegeneration), and playing a central role in pathogenesis of several major neurodegenerative disorders associated with parkinsonism
  • potential role in the biogenesis and/or regulation of vesicular and membranous intracellular structures within the mammalian brain
  • involved in membrane trafficking system, and playing an important role in axon guidance during development
  • playing a potential role in the biogenesis and/or regulation of vesicular and membranous intracellular structures within the brain
  • regulates neurite maintenance and neuronal survival
  • GTPase domain of LRRK2 plays an important role in the regulation of kinase activity
  • first mammalian ROCO protein that is an authentic and functional GTPase and that may play a central role in integrating pathways involved in neuronal cell signaling and the pathogenesis of Parkinson disease
  • possible redundancy in the cerebral function between LRRK1 and LRRK2
  • its kinase and GTPase activities may exhibit complex autoregulatory interdependence
  • involved in the endosomal–autophagic pathway and the recruitment to specific membrane microdomains (suggesting a novel function for this important Parkinson-related protein)
  • in conjunction with its interaction with RAB5B, plays an important role in synaptic function by modulating the endocytosis of synaptic vesicles
  • a role for LRRK2 in striatal dopamine transmission and the consequent motor function (
  • a pivotal role in regulating striatal dopamin transmission and consequent control of motor function (
  • plays an essential role in the regulation of protein homeostasis during aging (
  • LRRK2 dimer possesses greater kinase activity than its more abundant monomeric counterpart
  • may impact on tau processing which subsequently leads to increased phosphorylation (
  • involved in diverse cell biological functions, including translational control, mitogen-activated protein kinase, TNF/FASLG and Wnt signaling pathways
  • role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity
  • regulates the cell protein translation machinery in diverse species and tissues
  • may be involved in vesicular trafficking by regulating membrane-bound proteins
  • its overexpression induces the formation of autophagosomes through a Ca2+/CaMKK/AMPK pathway (PMISD: 22012985)
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS neurogenesis
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
  • interacts with the microRNA (miRNA) pathway to regulate protein synthesis
  • small molecule
    protein
  • C-terminal R2 ring-finger domain of parkin
  • RAB5B
  • carboxy terminus of Hsp70-interacting protein, CHIP (
  • phosphorylate recombinant alpha synuclein at serine 129
  • alpha-synuclein, SNCA
  • MAPK kinases 3, 6, and 7 (
  • associated with human Argonaute-2 (hAgo2) of the RNA-induced silencing complex (RISC)
  • interacting with MET (MET and LRRK2 cooperate to promote efficient tumor cell growth and survival in the papillary renal and thyroid carcinomas)
  • interaction between LRRK2 and the Rho GTPase, RAC1, which plays a critical role in actin cytoskeleton remodeling necessary for the maintenance of neurite morphology (LRRK2 binds RAC1 via the ROC-COR kinase domains, supporting the hypothesis that LRRK2 is forming a heterodimer with RAC1 through the ROC-COR kinase domain)
  • binds the small GTPase Rab1A as well as the F-actin cross-linking protein filamin (actin-binding protein 120, abp120)
  • cell & other assembled microtubules (
    REGULATION
    inhibited by Y-27632 and H-1152, inhibitors of the Roh-associated protein kinases
    Other autophosphorylation
    LRRK2 kinase activity is regulated by GTP via the intrinsic GTPase Roc domain ,
    activated in response to chemoattractant stimulation and helps mediate cell polarization and chemotaxis by regulating cortical F-actin polymerization and pseudopod extension in a pathway that requires RAB1A
    ASSOCIATED DISORDERS
    corresponding disease(s) PARK8
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    mutation Gly2019Ser enhances catalytic activity
    tumoral     --over  
    with MET protein kinases in papillary renal cell carcinoma and in papillary thyroid carcinoma
    Susceptibility to sporadic Parkinson disease
    Variant & Polymorphism SNP increasing the risk of sporadic Parkinson disease
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    may be a target for future therapeutic intervention in Parkinson disease
    neurologyneurodegenerativeParkinson/dementia Parkinsonism
    inhibition of LRRK2 expression is a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration
    cancerurinary 
    targeting LRRK2 may be an attractive pharmacologic strategy to complement MET inhibitors in patients with specific papillary tumors or to treat patients with germ-line LRRK2 mutations that predispose them to both Parkinson disease and epithelial cancers
    ANIMAL & CELL MODELS
  • mutant LRRK2 causes neuronal degeneration in both SH-SY5Y cells and primary neurons
  • neurons expressing disease-associated mutant forms of LRRK2 display reduced neurite process length and complexity, tau-positive inclusions with lysosomal features, and ultimately apoptotic cell death
  • neurons deficient in LRRK2 harbor extended neuritic processes with increased branching
  • transgenic Drosophila expressing LRRK2-G2019S mutation display retinal degeneration, selective loss of dopaminergic neurons, locomotor dysfunction, more severe parkinsonism and early mortality
  • LRRK2 transgenic mouse model display an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection (
  • transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice (
  • transgenic mouse strains overexpressing LRRK2 wild-type have elevated striatal dopamine (DA) release with unaltered DA uptake or tissue content, are hyperactive and show enhanced performance in motor function tests (
  • transgenic mouse strains overexpressing LRRK2 mutant G2019S display an age-dependent decrease in striatal dopamin content, as well as decreased striatal dopamin release and uptake (
  • dopaminergic system of LRRK2(-/-) mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged but LRRK2(-/-) kidneys develop striking accumulation and aggregation of alpha-synuclein and ubiquitinated proteins at 20 months of age. loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage (
  • abnormal dopamine neurotransmission in both hWT and G2019S transgenic LRRK2 mice evidenced by a decrease in extra-cellular dopamine levels (
  • Mice completely lacking the LRRK2 protein (KO) showed an early-onset marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells
  • Mice expressing a LRRK2 kinase-dead mutant (KD) from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung and had had dramatically reduced full-length LRRK2 protein levels in the kidney
  • Knock-in (KI) mice expressing the G2019S PD-associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice