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LRRK2

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LRRK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLRRK2, AURA17, DARDARIN, PARK8, RIPK7, ROCO2, leucine-rich repeat kinase 2, leucine rich repeat kinase 2
External IDsOMIM: 609007; MGI: 1913975; HomoloGene: 18982; GeneCards: LRRK2; OMA:LRRK2 - orthologs
EC number2.7.11.1
Orthologs
SpeciesHumanMouse
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 MbChr 15: 91.56 – 91.7 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]

Function

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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 p47phox subunit of NOX2 at S345.[19]

Clinical significance

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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]

Therapeutics development

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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]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000188906 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000036273 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, et al. (November 2004). "Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease". Neuron. 44 (4): 595–600. doi:10.1016/j.neuron.2004.10.023. PMID 15541308. S2CID 16688488.
  6. ^ a b Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. (November 2004). "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology". Neuron. 44 (4): 601–607. doi:10.1016/j.neuron.2004.11.005. PMID 15541309. S2CID 8642468.
  7. ^ Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, et al. (December 2005). "Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration". Proceedings of the National Academy of Sciences of the United States of America. 102 (51): 18676–18681. Bibcode:2005PNAS..10218676S. doi:10.1073/pnas.0508052102. PMC 1317945. PMID 16352719.
  8. ^ MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A (November 2006). "The familial Parkinsonism gene LRRK2 regulates neurite process morphology". Neuron. 52 (4): 587–593. doi:10.1016/j.neuron.2006.10.008. PMID 17114044. S2CID 16966163.
  9. ^ Plowey ED, Cherra SJ, Liu YJ, Chu CT (May 2008). "Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells". Journal of Neurochemistry. 105 (3): 1048–1056. doi:10.1111/j.1471-4159.2008.05217.x. PMC 2361385. PMID 18182054.
  10. ^ Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, et al. (May 2012). "Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain". The Journal of Neuroscience. 32 (22): 7585–7593. doi:10.1523/JNEUROSCI.5809-11.2012. PMC 3382107. PMID 22649237.
  11. ^ Gómez-Suaga P, Luzón-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, et al. (February 2012). "Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP". Human Molecular Genetics. 21 (3): 511–525. doi:10.1093/hmg/ddr481. PMC 3259011. PMID 22012985.
  12. ^ Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, et al. (April 2011). Cai H (ed.). "Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2". PloS One. 6 (4): e18568. Bibcode:2011PLoSO...618568R. doi:10.1371/journal.pone.0018568. PMC 3071839. PMID 21494637.
  13. ^ Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, et al. (November 2009). "LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model". Human Molecular Genetics. 18 (21): 4022–4034. doi:10.1093/hmg/ddp346. PMC 2758136. PMID 19640926.
  14. ^ Cherra SJ, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, et al. (August 2010). "Regulation of the autophagy protein LC3 by phosphorylation". The Journal of Cell Biology. 190 (4): 533–539. doi:10.1083/jcb.201002108. PMC 2928022. PMID 20713600.
  15. ^ Cherra SJ, Steer E, Gusdon AM, Kiselyov K, Chu CT (February 2013). "Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons". The American Journal of Pathology. 182 (2): 474–484. doi:10.1016/j.ajpath.2012.10.027. PMC 3562730. PMID 23231918.
  16. ^ Orenstein SJ, Kuo SH, Tasset I, Arias E, Koga H, Fernandez-Carasa I, et al. (April 2013). "Interplay of LRRK2 with chaperone-mediated autophagy". Nature Neuroscience. 16 (4): 394–406. doi:10.1038/nn.3350. PMC 3609872. PMID 23455607.
  17. ^ West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, et al. (November 2005). "Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity". Proceedings of the National Academy of Sciences of the United States of America. 102 (46): 16842–16847. doi:10.1073/pnas.0507360102. PMC 1283829. PMID 16269541.
  18. ^ Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, Meitinger T, et al. (January 2006). "The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity". Human Molecular Genetics. 15 (2): 223–232. doi:10.1093/hmg/ddi439. PMID 16321986.
  19. ^ Keeney MT, Rocha EM, Hoffman EK, Farmer K, Di Maio R, Weir J, et al. (October 2024). "LRRK2 regulates production of reactive oxygen species in cell and animal models of Parkinson's disease". Science Translational Medicine. 16 (767): eadl3438. doi:10.1126/scitranslmed.adl3438. PMID 39356746.
  20. ^ "Entrez Gene: LRRK2 leucine-rich repeat kinase 2".
  21. ^ Shapiro L (2023-09-18). "Researchers win Breakthrough Prize for Parkinson's genetics discoveries | Parkinson's News Today". parkinsonsnewstoday.com. Retrieved 2023-09-20.
  22. ^ Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, et al. (February 2005). "A common LRRK2 mutation in idiopathic Parkinson's disease". Lancet. 365 (9457): 415–416. doi:10.1016/S0140-6736(05)17830-1. PMID 15680457. S2CID 36186136.
  23. ^ Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, et al. (July 2008). "Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study". The Lancet. Neurology. 7 (7): 583–590. doi:10.1016/S1474-4422(08)70117-0. PMC 2832754. PMID 18539534.
  24. ^ Lesage S, Dürr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, et al. (January 2006). "LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs". The New England Journal of Medicine. 354 (4): 422–423. doi:10.1056/NEJMc055540. PMID 16436781.
  25. ^ Manolio TA (July 2010). "Genomewide association studies and assessment of the risk of disease". The New England Journal of Medicine. 363 (2): 166–176. doi:10.1056/NEJMra0905980. PMID 20647212.
  26. ^ Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, et al. (February 2011). "Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies". Lancet. 377 (9766): 641–649. doi:10.1016/S0140-6736(10)62345-8. PMC 3696507. PMID 21292315.
  27. ^ Carreau M (November 14, 2018). "ISS Cargo Missions To Test Soyuz, Deliver New Science". 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.
  28. ^ “Young-Onset Parkinson's.” Parkinson's Foundation, 2 Oct. 2018, www.parkinson.org/Understanding-Parkinsons/What-is-Parkinsons/Young-Onset-Parkinsons.
  29. ^ Daher JP, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB (June 2014). "Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats". Proceedings of the National Academy of Sciences of the United States of America. 111 (25): 9289–9294. doi:10.1073/pnas.1403215111. PMC 4078806. PMID 24927544.
  30. ^ 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". The Journal of Biological Chemistry. 290 (32): 19433–19444. doi:10.1074/jbc.M115.660001. PMC 4528108. PMID 26078453.
  31. ^ 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:10.1126/scitranslmed.abj2658. PMID 35675433.
  32. ^ 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:10.1002/mds.29297. hdl:1887/3748181. PMID 36807624.
  33. ^ 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". Molecular Therapy. Nucleic Acids. 8: 508–519. doi:10.1016/j.omtn.2017.08.002. PMC 5573879. PMID 28918051.

Further reading

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