LRRK2

LRRK2
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2ZEJ, 3D6T
Identifiers
Aliases	LRRK2, AURA17, DARDARIN, PARK8, RIPK7, ROCO2, leucine-rich repeat kinase 2, leucine rich repeat kinase 2
External IDs	OMIM: 609007; MGI: 1913975; HomoloGene: 18982; GeneCards: LRRK2; OMA:LRRK2 - orthologs
EC number	2.7.11.1
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q12 Start 40,196,744 bp[1] End 40,369,285 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 E3 Start 91,557,378 bp[2] End 91,700,323 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell monocyte lower lobe of lung blood upper lobe of lung upper lobe of left lung right lung Achilles tendon granulocyte visceral pleura Top expressed in granulocyte human kidney proximal tubule left lung left lung lobe right kidney superior frontal gyrus lumbar spinal ganglion spleen right lung More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity signaling receptor complex adaptor activity clathrin binding co-receptor binding transferase activity GTPase activator activity protein kinase activity protein kinase A binding peroxidase inhibitor activity SNARE binding nucleotide binding identical protein binding GTPase activity syntaxin-1 binding protein serine/threonine kinase activity tubulin binding transmembrane transporter binding microtubule binding MAP kinase kinase activity GTP binding ATP binding GTP-dependent protein kinase activity beta-catenin destruction complex binding protein binding kinase activity actin binding magnesium ion binding Cellular component cytoplasmic vesicle endosome extracellular exosome Wnt signalosome soma trans-Golgi network mitochondrial membranes synapse cytoplasm mitochondrial outer membrane synaptic vesicle membrane perikaryon endoplasmic reticulum plasma membrane microvillus mitochondrial matrix dendrite cytoplasm growth cone cell projection dendrite lysosome neuron projection Golgi-associated vesicle mitochondrion mitochondrial inner membrane autolysosome terminal bouton intracellular anatomical structure membrane membrane raft axon amphisome multivesicular body, internal vesicle synaptic vesicle inclusion body cell junction cytoplasmic side of mitochondrial outer membrane cytosol Golgi apparatus postsynapse extracellular space nucleus intracellular membrane-bounded organelle caveola neck endoplasmic reticulum exit site glutamatergic synapse presynaptic cytosol ribonucleoprotein complex Biological process lysosome organization response to oxidative stress cellular response to dopamine regulation of autophagy positive regulation of autophagy positive regulation of dopamine receptor signaling pathway regulation of neuroblast proliferation intracellular distribution of mitochondria negative regulation of protein processing negative regulation of protein processing involved in protein targeting to mitochondrion protein localization to mitochondrion positive regulation of canonical Wnt signaling pathway autophagy neuromuscular junction development phosphorylation positive regulation of protein binding regulation of branching morphogenesis of a nerve mitochondrion localization positive regulation of protein autoubiquitination regulation of synaptic vesicle transport positive regulation of protein phosphorylation regulation of kidney size regulation of synaptic vesicle exocytosis positive regulation of MAP kinase activity peptidyl-threonine phosphorylation MAPK cascade Wnt signalosome assembly protein phosphorylation regulation of synaptic transmission, glutamatergic excitatory postsynaptic potential negative regulation of hydrogen peroxide-induced cell death regulation of dopamine receptor signaling pathway regulation of membrane potential protein autophosphorylation regulation of mitochondrial fission regulation of neuron maturation reactive oxygen species metabolic process positive regulation of programmed cell death regulation of neuron death regulation of mitochondrial depolarization cellular response to oxidative stress negative regulation of late endosome to lysosome transport intracellular signal transduction regulation of lysosomal lumen pH negative regulation of GTPase activity locomotory exploration behavior Golgi organization canonical Wnt signaling pathway neuron projection morphogenesis positive regulation of protein ubiquitination regulation of canonical Wnt signaling pathway exploration behavior cellular response to organic cyclic compound tangential migration from the subventricular zone to the olfactory bulb regulation of protein kinase A signaling calcium-mediated signaling negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway positive regulation of proteasomal ubiquitin-dependent protein catabolic process negative regulation of neuron death negative regulation of protein targeting to mitochondrion peptidyl-serine phosphorylation determination of adult lifespan negative regulation of excitatory postsynaptic potential negative regulation of protein phosphorylation neuron death GTP metabolic process negative regulation of autophagosome assembly olfactory bulb development cellular response to starvation regulation of dendritic spine morphogenesis cell differentiation endocytosis negative regulation of protein binding mitochondrion organization cellular response to manganese ion negative regulation of macroautophagy regulation of locomotion positive regulation of GTPase activity regulation of retrograde transport, endosome to Golgi regulation of CAMKK-AMPK signaling cascade positive regulation of histone deacetylase activity endoplasmic reticulum organization spermatogenesis regulation of gene expression negative regulation of neuron projection development striatum development regulation of protein stability positive regulation of nitric-oxide synthase biosynthetic process regulation of ER to Golgi vesicle-mediated transport protein localization to endoplasmic reticulum exit site neuron projection arborization regulation of synaptic vesicle endocytosis positive regulation of synaptic vesicle endocytosis positive regulation of microglial cell activation protein import into nucleus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 120892 66725 Ensembl ENSG00000188906 ENSMUSG00000036273 UniProt Q5S007 Q5S006 RefSeq (mRNA) NM_198578 NM_025730 RefSeq (protein) NP_940980 NP_080006 Location (UCSC) Chr 12: 40.2 – 40.37 Mb Chr 15: 91.56 – 91.7 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Leucine-rich repeat kinase 2 (LRRK2), also known as dardarin (from the Basque word "dardara" which means trembling) and PARK8 (from early identified association with Parkinson's disease), is a large, multifunctional kinase enzyme that in humans is encoded by the LRRK2 gene.^[5][6] LRRK2 is a member of the leucine-rich repeat kinase family. Variants of this gene are associated with an increased risk of Parkinson's disease and Crohn's disease.^[5][6]

The LRRK2 gene encodes a protein with an armadillo repeats (ARM) region, an ankyrin repeat (ANK) region, a leucine-rich repeat (LRR) domain, a kinase domain, a RAS domain, a GTPase domain, and a WD40 domain. The protein is present largely in the cytoplasm but also associates with the mitochondrial outer membrane.

LRRK2 interacts with the C-terminal R2 RING finger domain of parkin, and parkin interacted with the COR domain of LRRK2. Expression of mutant LRRK2 induced apoptotic cell death in neuroblastoma cells and in mouse cortical neurons.^[7]

Expression of LRRK2 mutants implicated in autosomal dominant Parkinson's disease causes shortening and simplification of the dendritic tree in vivo and in cultured neurons.^[8] This is mediated in part by alterations in macroautophagy,^{[9][10][11][12][13]} and can be prevented by protein kinase A regulation of the autophagy protein LC3.^[14] The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.^[15] LRRK2 is also a substrate for chaperone-mediated autophagy.^[16]

Disease-associated mutant alleles of LRRK2 (R1441C, G2019S, I2020T) generally show elevated kinase activity.^[17][18]

LRRK2 activity has been tied to generation of reactive-oxygen species (ROS) which are associated with Parkinson's disease pathogenesis. This activity is dependent on LRRK2-mediated phosphorylation of NADPH oxidase 2 (NOX2). Specifically, LRRK2 activity promotes activatory phosphorylation of the p47^phox subunit of NOX2 at S345.^[19]

Mutations in this gene have been associated with Parkinson's disease type 8.^[20][21]

The G2019S mutation results in enhanced kinase activity, and is a relatively common cause of familial Parkinson's disease in Caucasians.^[22] It may also cause sporadic Parkinson's disease. The mutated Gly amino acid is conserved in all kinase domains of all species.

The G2019S mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease. Of these, G2019S is the most common in the Western World, accounting for ~2% of all Parkinson's disease cases in North American Caucasians. This mutation is enriched in certain populations, being found in approximately 20% of all Ashkenazi Jewish Parkinson's disease patients and in approximately 40% of all Parkinson's disease patients of North African Berber Arab ancestry.^[23][24]

Unexpectedly, genome-wide association studies have found an association between LRRK2 and Crohn's disease as well as with Parkinson's disease, suggesting that the two diseases share common pathways.^[25][26]

Attempts have been made to grow crystals of the LRRK2 aboard the International Space Station, as the low-gravity environment renders the protein less susceptible to sedimentation and convection, and thus more crystallizable.^[27]

Mutations in the LRRK2 gene is the main factor in contributing to the genetic development of Parkinson's disease, and over 100 mutations in this gene have been shown to increase the chance of PD development. These mutations are most commonly seen in North African Arab Berber, Chinese, and Japanese populations.^[28]

Multiple preclinical studies have found that inhibition or silencing of LRRK2 may be therapeutically beneficial for treatment of Parkinson's disease.^[29][30] There have been efforts to develop therapeutics for Parkinson's disease targeting LRRK2, including LRRK2 inhibitors^[31][32] and antisense oligonucleotides (ASOs) targeting LRRK2.^[33]

• GeneReviews/NCBI/NIH/UW entry on LRRK2-Related Parkinson Disease
• LRRK2+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)