# LRRK2

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Protein kinase found in humans

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](/source/Kinase) [enzyme](/source/Enzyme) that in humans is encoded by the *LRRK2* [gene](/source/Gene).[5][6] LRRK2 is a member of the [leucine-rich repeat](/source/Leucine-rich_repeat) kinase family. Variants of this gene are associated with an increased risk of [Parkinson's disease](/source/Parkinson's_disease) and [Crohn's disease](/source/Crohn's_disease).[5][6]

## Function

The LRRK2 gene encodes a [protein](/source/Protein) with an [armadillo repeats](/source/Armadillo_repeats) (ARM) region, an [ankyrin repeat](/source/Ankyrin_repeat) (ANK) region, a [leucine-rich repeat](/source/Leucine-rich_repeat) (LRR) domain, a [kinase](/source/Kinase) domain, a RAS domain, a [GTPase](/source/GTPase) domain, and a [WD40](/source/WD40_repeat) domain. Possible cellular functions of LRRK2 include the cytoskeleton, membrane trafficking, iron homoeostasis and [mitochondrial function](/source/Outer_mitochondrial_membrane).[7]

LRRK2 interacts with the [C-terminal](/source/C-terminus) R2 [RING finger domain](/source/RING_finger_domain) of [parkin](/source/Parkin_(ligase)), and parkin interacted with the COR domain of LRRK2. Expression of mutant LRRK2 induced [apoptotic](/source/Apoptotic) cell death in neuroblastoma cells and in mouse cortical neurons.[8]

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.[9] This is mediated in part by alterations in macroautophagy,[10][11][12][13][14] and can be prevented by protein kinase A regulation of the autophagy protein LC3.[15] The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.[16] LRRK2 is also a substrate for chaperone-mediated autophagy.[17]

Disease-associated mutant alleles of LRRK2 (R1441C, G2019S, I2020T) generally show elevated kinase activity.[18][19]

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)](/source/NOX2). Specifically, LRRK2 activity promotes activatory phosphorylation of the p47phox subunit of NOX2 at S345.[20]

## Clinical significance

[Mutations](/source/Mutation) in this gene have been associated with [Parkinson's disease](/source/Parkinson's_disease) type 8.[21][22]

The G2019S mutation results in enhanced kinase activity, and is a relatively common cause of familial Parkinson's disease in Caucasians.[23] 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](/source/Ashkenazi_Jews) Parkinson's disease patients and in approximately 40% of all Parkinson's disease patients of [North African](/source/North_Africa) [Berber](/source/Berbers) Arab ancestry.[24][25]

Unexpectedly, genome-wide association studies have found an association between LRRK2 and [Crohn's disease](/source/Crohn's_disease) as well as with Parkinson's disease, suggesting that the two diseases share common pathways.[26][27]

Attempts have been made to grow crystals of the LRRK2 aboard the [International Space Station](/source/International_Space_Station), as the low-gravity environment renders the protein less susceptible to sedimentation and convection, and thus more crystallizable.[28]

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.[29]

### Therapeutics development

Multiple preclinical studies have found that inhibition or silencing of LRRK2 may be therapeutically beneficial for treatment of Parkinson's disease.[30][31] There have been efforts to develop therapeutics for Parkinson's disease targeting LRRK2, including LRRK2 inhibitors[32][33] and antisense oligonucleotides (ASOs) targeting LRRK2.[34]

In May 2026, [Denali](/source/Denali_(disambiguation)) and [Biogen](/source/Biogen) halted development of BIIB122 after a clinical trial failed to meet its primary or secondary endpoints, despite success at inhibiting LRRK2 kinase. Other clinical trials continued.[35]

## References

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1. **[^](#cite_ref-28)** Carreau M (November 14, 2018). ["ISS Cargo Missions To Test Soyuz, Deliver New Science"](http://aviationweek.com/space/iss-cargo-missions-test-soyuz-deliver-new-science?NL=AW-05&Issue=AW-05_20181115_AW-05_73&sfvc4enews=42&cl=article_4&elq2=1baf6ee9720c435fbb2cf9def871857e). *[Aviation Week](/source/Aviation_Week)*. A collaboration between the Michael J. Fox Foundation, of New York City, and Merck Research Laboratories, of Kenilworth, New Jersey, will seek to grow crystals of a key gene protein, Leucine-Rich Repeat Kinase 2 (LRRK2), in an effort to advance the search for a cure for Parkinson's disease. Crystals cultured in the absence of gravity are less susceptible to sedimentation and convection, rendering them larger and easier to map than those grown in labs on Earth in order to design medicines.

1. **[^](#cite_ref-29)** "Young-Onset Parkinson's." Parkinson's Foundation, 2 Oct. 2018, www.parkinson.org/Understanding-Parkinsons/What-is-Parkinsons/Young-Onset-Parkinsons.

1. **[^](#cite_ref-30)** Daher JP, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB (June 2014). ["Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078806). *Proceedings of the National Academy of Sciences of the United States of America*. **111** (25): 9289–9294. [Bibcode](/source/Bibcode_(identifier)):[2014PNAS..111.9289D](https://ui.adsabs.harvard.edu/abs/2014PNAS..111.9289D). [doi](/source/Doi_(identifier)):[10.1073/pnas.1403215111](https://doi.org/10.1073%2Fpnas.1403215111). [PMC](/source/PMC_(identifier)) [4078806](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078806). [PMID](/source/PMID_(identifier)) [24927544](https://pubmed.ncbi.nlm.nih.gov/24927544).

1. **[^](#cite_ref-31)** Daher JP, Abdelmotilib HA, Hu X, Volpicelli-Daley LA, Moehle MS, Fraser KB, et al. (August 2015). ["Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528108). *The Journal of Biological Chemistry*. **290** (32): 19433–19444. [doi](/source/Doi_(identifier)):[10.1074/jbc.M115.660001](https://doi.org/10.1074%2Fjbc.M115.660001). [PMC](/source/PMC_(identifier)) [4528108](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528108). [PMID](/source/PMID_(identifier)) [26078453](https://pubmed.ncbi.nlm.nih.gov/26078453).

1. **[^](#cite_ref-32)** Jennings D, Huntwork-Rodriguez S, Henry AG, Sasaki JC, Meisner R, Diaz D, et al. (June 2022). "Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease". *Science Translational Medicine*. **14** (648) eabj2658. [doi](/source/Doi_(identifier)):[10.1126/scitranslmed.abj2658](https://doi.org/10.1126%2Fscitranslmed.abj2658). [PMID](/source/PMID_(identifier)) [35675433](https://pubmed.ncbi.nlm.nih.gov/35675433).

1. **[^](#cite_ref-33)** Jennings D, Huntwork-Rodriguez S, Vissers MF, Daryani VM, Diaz D, Goo MS, et al. (March 2023). "LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease". *Movement Disorders*. **38** (3): 386–398. [doi](/source/Doi_(identifier)):[10.1002/mds.29297](https://doi.org/10.1002%2Fmds.29297). [hdl](/source/Hdl_(identifier)):[1887/3748181](https://hdl.handle.net/1887%2F3748181). [PMID](/source/PMID_(identifier)) [36807624](https://pubmed.ncbi.nlm.nih.gov/36807624).

1. **[^](#cite_ref-34)** Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, et al. (September 2017). ["LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573879). *Molecular Therapy. Nucleic Acids*. **8**: 508–519. [doi](/source/Doi_(identifier)):[10.1016/j.omtn.2017.08.002](https://doi.org/10.1016%2Fj.omtn.2017.08.002). [PMC](/source/PMC_(identifier)) [5573879](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573879). [PMID](/source/PMID_(identifier)) [28918051](https://pubmed.ncbi.nlm.nih.gov/28918051).

1. **[^](#cite_ref-35)** Biogen (2026-05-21). ["Biogen and Denali Therapeutics Provide Update on Phase 2b LUMA Study of BIIB122 (DNL151) in Early-Stage Parkinson's Disease"](https://www.globenewswire.com/news-release/2026/05/21/3299820/0/en/Biogen-and-Denali-Therapeutics-Provide-Update-on-Phase-2b-LUMA-Study-of-BIIB122-DNL151-in-Early-Stage-Parkinson-s-Disease.html). *GlobeNewswire News Room*. Retrieved 2026-05-22.

## Further reading

- Singleton AB (August 2005). "Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin". *Trends in Neurosciences*. **28** (8): 416–421. [doi](/source/Doi_(identifier)):[10.1016/j.tins.2005.05.009](https://doi.org/10.1016%2Fj.tins.2005.05.009). [PMID](/source/PMID_(identifier)) [15955578](https://pubmed.ncbi.nlm.nih.gov/15955578). [S2CID](/source/S2CID_(identifier)) [53204736](https://api.semanticscholar.org/CorpusID:53204736).

- Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA (May 2006). "LRRK2 in Parkinson's disease: protein domains and functional insights". *Trends in Neurosciences*. **29** (5): 286–293. [doi](/source/Doi_(identifier)):[10.1016/j.tins.2006.03.006](https://doi.org/10.1016%2Fj.tins.2006.03.006). [PMID](/source/PMID_(identifier)) [16616379](https://pubmed.ncbi.nlm.nih.gov/16616379). [S2CID](/source/S2CID_(identifier)) [11458231](https://api.semanticscholar.org/CorpusID:11458231).

- Haugarvoll K, Wszolek ZK (July 2006). "PARK8 LRRK2 parkinsonism". *Current Neurology and Neuroscience Reports*. **6** (4): 287–294. [doi](/source/Doi_(identifier)):[10.1007/s11910-006-0020-0](https://doi.org/10.1007%2Fs11910-006-0020-0). [PMID](/source/PMID_(identifier)) [16822348](https://pubmed.ncbi.nlm.nih.gov/16822348). [S2CID](/source/S2CID_(identifier)) [25252449](https://api.semanticscholar.org/CorpusID:25252449).

- Bonifati V (September 2006). "The pleomorphic pathology of inherited Parkinson's disease: lessons from LRRK2". *Current Neurology and Neuroscience Reports*. **6** (5): 355–357. [doi](/source/Doi_(identifier)):[10.1007/s11910-996-0013-z](https://doi.org/10.1007%2Fs11910-996-0013-z). [PMID](/source/PMID_(identifier)) [16928343](https://pubmed.ncbi.nlm.nih.gov/16928343). [S2CID](/source/S2CID_(identifier)) [41352829](https://api.semanticscholar.org/CorpusID:41352829).

- Schapira AH (September 2006). "The importance of LRRK2 mutations in Parkinson disease". *Archives of Neurology*. **63** (9): 1225–1228. [doi](/source/Doi_(identifier)):[10.1001/archneur.63.9.1225](https://doi.org/10.1001%2Farchneur.63.9.1225). [PMID](/source/PMID_(identifier)) [16966498](https://pubmed.ncbi.nlm.nih.gov/16966498).

- Whaley NR, Uitti RJ, Dickson DW, Farrer MJ, Wszolek ZK (2006). "Clinical and pathologic features of families with LRRK2-associated Parkinson's disease". *Parkinson's Disease and Related Disorders*. pp. 221–229. [doi](/source/Doi_(identifier)):[10.1007/978-3-211-45295-0_34](https://doi.org/10.1007%2F978-3-211-45295-0_34). [ISBN](/source/ISBN_(identifier)) [978-3-211-28927-3](https://en.wikipedia.org/wiki/Special:BookSources/978-3-211-28927-3). [PMID](/source/PMID_(identifier)) [17017533](https://pubmed.ncbi.nlm.nih.gov/17017533). {{[cite book](https://en.wikipedia.org/wiki/Template:Cite_book)}}: |journal= ignored ([help](https://en.wikipedia.org/wiki/Help:CS1_errors#periodical_ignored))

- Gasser T (2006). "Molecular genetic findings in LRRK2 American, Canadian and German families". *Parkinson's Disease and Related Disorders*. pp. 231–234. [doi](/source/Doi_(identifier)):[10.1007/978-3-211-45295-0_35](https://doi.org/10.1007%2F978-3-211-45295-0_35). [ISBN](/source/ISBN_(identifier)) [978-3-211-28927-3](https://en.wikipedia.org/wiki/Special:BookSources/978-3-211-28927-3). [PMID](/source/PMID_(identifier)) [17017534](https://pubmed.ncbi.nlm.nih.gov/17017534). {{[cite book](https://en.wikipedia.org/wiki/Template:Cite_book)}}: |journal= ignored ([help](https://en.wikipedia.org/wiki/Help:CS1_errors#periodical_ignored))

- Tan EK (November 2006). ["Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease"](https://doi.org/10.47102%2Fannals-acadmedsg.V35N11p840). *Annals of the Academy of Medicine, Singapore*. **35** (11): 840–842. [doi](/source/Doi_(identifier)):[10.47102/annals-acadmedsg.V35N11p840](https://doi.org/10.47102%2Fannals-acadmedsg.V35N11p840). [PMID](/source/PMID_(identifier)) [17160203](https://pubmed.ncbi.nlm.nih.gov/17160203).

## External links

- [GeneReviews/NCBI/NIH/UW entry on LRRK2-Related Parkinson Disease](https://www.ncbi.nlm.nih.gov/books/NBK1208/)

- [LRRK2+protein,+human](https://meshb.nlm.nih.gov/record/ui?name=LRRK2+protein%2C+human) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

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Adapted from the Wikipedia article [LRRK2](https://en.wikipedia.org/wiki/LRRK2) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/LRRK2?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.