LRRK2

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 kinase enzyme that in humans is encoded by the LRRK2 gene.[5] 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 also Crohn's disease.[5][6]

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
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 91,673,175 bp[2] End 91,816,120 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • protein homodimerization activity • receptor signaling complex scaffold activity • clathrin binding • co-receptor binding • transferase activity • GO:0005097, GO:0005099, GO:0005100 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 • Rho GTPase binding • tubulin binding • ion channel binding • microtubule binding • MAP kinase kinase activity • GTP binding • ATP binding • GTP-dependent protein kinase activity • beta-catenin destruction complex binding • GO:0001948 protein binding • kinase activity • actin binding • magnesium ion binding Cellular component • cytoplasmic vesicle • endosome • extracellular exosome • Wnt signalosome • neuronal cell body • trans-Golgi network • mitochondrial membranes • synapse • cytoplasm • mitochondrial outer membrane • synaptic vesicle membrane • perikaryon • endoplasmic reticulum • cell membrane • microvilli • mitochondrial matrix • dendrite cytoplasm • growth cone • cell projection • dendrite • lysosome • neuron projection • Golgi-associated vesicle • mitochondrion • mitochondrial inner membrane • autolysosome • terminal bouton • intracellular • 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 • cell nucleus • intracellular membrane-bounded organelle • caveola neck • endoplasmic reticulum exit site • glutamatergic synapse • presynaptic cytosol • ribonucleoprotein 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 • cellular protein localization • 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 • 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 • activation of MAPK activity • negative regulation of late endosome to lysosome transport • activation of MAPKK activity • GO:0007243 intracellular signal transduction • regulation of lysosomal lumen pH • GO:0034259 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 • GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 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 • positive regulation of tumor necrosis factor secretion • 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: 91.67 – 91.82 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

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]

Clinical significance

Mutations in this gene have been associated with Parkinson's disease type 8.[17]

The Gly2019Ser mutation results in enhanced kinase activity, and is a relatively common cause of familial Parkinson's disease in Caucasians.[18] It may also cause sporadic Parkinson's disease. The mutated Gly amino acid is conserved in all kinase domains of all species.

The Gly2019Ser mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease. Of these, Gly2019Ser 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.[19][20]

Unexpectedly, genomewide 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.[21][22]

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.[23]

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 Jewish, North African Arab Berber, Chinese, and Japanese populations.[24]

References

1. GRCh38: Ensembl release 89: ENSG00000188906 - Ensembl, May 2017
2. 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. Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, López de Munain A, Aparicio S, Gil AM, Khan N, Johnson J, Martinez JR, Nicholl D, Carrera IM, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB (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.
6. Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Müller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T (November 2004). "Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology". Neuron. 44 (4): 601–7. doi:10.1016/j.neuron.2004.11.005. PMID 15541309.
7. Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA (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): 18676–81. 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): 587–93. doi:10.1016/j.neuron.2006.10.008. PMID 17114044.
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): 1048–56. 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, Holstein GR, Yue Z (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): 7585–93. 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, Woodman PG, Churchill GC, Hilfiker S (February 2012). "Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP". Human Molecular Genetics. 21 (3): 511–25. doi:10.1093/hmg/ddr481. PMC 3259011. PMID 22012985.
12. Ramonet D, Daher JP, Lin BM, Stafa K, Kim J, Banerjee R, Westerlund M, Pletnikova O, Glauser L, Yang L, Liu Y, Swing DA, Beal MF, Troncoso JC, McCaffery JM, Jenkins NA, Copeland NG, Galter D, Thomas B, Lee MK, Dawson TM, Dawson VL, Moore DJ (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, Wade-Martins R (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): 4022–34. doi:10.1093/hmg/ddp346. PMC 2758136. PMID 19640926.
14. Cherra SJ, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT (August 2010). "Regulation of the autophagy protein LC3 by phosphorylation". The Journal of Cell Biology. 190 (4): 533–9. 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): 474–84. 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, Cortes E, Honig LS, Dauer W, Consiglio A, Raya A, Sulzer D, Cuervo AM (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. "Entrez Gene: LRRK2 leucine-rich repeat kinase 2".
18. Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP, Lynch J, Healy DG, Holton JL, Revesz T, Wood NW (February 2005). "A common LRRK2 mutation in idiopathic Parkinson's disease". Lancet. 365 (9457): 415–6. doi:10.1016/S0140-6736(05)17830-1. PMID 15680457.
19. 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): 583–90. doi:10.1016/S1474-4422(08)70117-0. PMC 2832754. PMID 18539534.
20. 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): 422–3. doi:10.1056/NEJMc055540. PMID 16436781.
21. Manolio TA (July 2010). "Genomewide association studies and assessment of the risk of disease". The New England Journal of Medicine. 363 (2): 166–76. doi:10.1056/NEJMra0905980. PMID 20647212.
22. Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simón-Sánchez J, Schulte C, Lesage S, Sveinbjörnsdóttir S, Stefánsson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW (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): 641–9. doi:10.1016/S0140-6736(10)62345-8. PMC 3696507. PMID 21292315.
23. Carreau, Mark (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.
24. “Young-Onset Parkinson's.” Parkinson's Foundation, 2 Oct. 2018, www.parkinson.org/Understanding-Parkinsons/What-is-Parkinsons/Young-Onset-Parkinsons.

Further reading

• Singleton AB (August 2005). "Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin". Trends in Neurosciences. 28 (8): 416–21. doi:10.1016/j.tins.2005.05.009. PMID 15955578.
• 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): 286–93. doi:10.1016/j.tins.2006.03.006. PMID 16616379.
• Haugarvoll K, Wszolek ZK (July 2006). "PARK8 LRRK2 parkinsonism". Current Neurology and Neuroscience Reports. 6 (4): 287–94. doi:10.1007/s11910-006-0020-0. PMID 16822348.
• Bonifati V (September 2006). "The pleomorphic pathology of inherited Parkinson's disease: lessons from LRRK2". Current Neurology and Neuroscience Reports. 6 (5): 355–7. doi:10.1007/s11910-996-0013-z. PMID 16928343.
• Schapira AH (September 2006). "The importance of LRRK2 mutations in Parkinson disease". Archives of Neurology. 63 (9): 1225–8. doi:10.1001/archneur.63.9.1225. PMID 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:10.1007/978-3-211-45295-0_34. ISBN 978-3-211-28927-3. PMID 17017533.
• Gasser, T. (2006). "Molecular genetic findings in LRRK2 American, Canadian and German families". Parkinson's Disease and Related Disorders. pp. 231–234. doi:10.1007/978-3-211-45295-0_35. ISBN 978-3-211-28927-3. PMID 17017534.
• Tan EK (November 2006). "Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease". Annals of the Academy of Medicine, Singapore. 35 (11): 840–2. PMID 17160203.

External links

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