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
Genetically Related Diseases
Parkinson's disease[1]
Gene ontology Molecular function • protein homodimerization activity • receptor signaling complex scaffold activity • clathrin binding • co-receptor binding • transferase activity • GTPase activator activity • protein kinase activity • protein kinase A binding • peroxidase inhibitor activity • glycoprotein binding • 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 • protein binding • kinase activity • actin binding Cellular component • cytoplasmic vesicle • endosome • intracellular ribonucleoprotein complex • extracellular exosome • Wnt signalosome • neuronal cell body • trans-Golgi network • mitochondrial membrane • synapse • cytoplasm • mitochondrial outer membrane • intracellular membrane-bounded organelle • synaptic vesicle membrane • perikaryon • endoplasmic reticulum • plasma membrane • microvillus • mitochondrial matrix • dendrite cytoplasm • growth cone • caveola • 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 • extracellular space • cytoplasmic side of mitochondrial outer membrane • cytosol • Golgi apparatus • postsynapse Biological process • lysosome organization • response to oxidative stress • small GTPase mediated signal transduction • 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 • regulation of calcium-mediated signaling • 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 • activation of MAPK activity • negative regulation of late endosome to lysosome transport • activation of MAPKK activity • 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 • negative regulation of peroxidase activity Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	120892	66725
Ensembl	ENSG00000188906	ENSMUSG00000036273
UniProt	Q5S007	Q5S006
RefSeq (mRNA)	NM_198578	NM_025730
RefSeq (protein)	NP_940980.3	NP_080006.3
Location (UCSC)	Chr 12: 40.2 – 40.37 Mb	Chr 15: 91.67 – 91.82 Mb
PubMed search	[2]	[3]
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), is an enzyme that in humans is encoded by the PARK8 gene.^[4] 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.^[4][5]

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.^[6]

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.^[7] This is mediated in part by alterations in macroautophagy,^{[8][9][10][11][12]} and can be prevented by protein kinase A regulation of the autophagy protein LC3.^[13] The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.^[14] LRRK2 is also a substrate for chaperone-mediated autophagy.^[15]

Clinical significance

Mutations in this gene have been associated with Parkinson's disease type 8.^[16]

The Gly2019Ser mutation in LRRK2 is a relatively common cause of familial Parkinson's Disease in Caucasians.^[17] 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.

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.^[18][19]

References

1. "Diseases that are genetically associated with LRRK2 view/edit references on wikidata".
2. "Human PubMed Reference:".
3. "Mouse PubMed Reference:".
4. 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.
5. 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.
6. 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". Proc. Natl. Acad. Sci. U.S.A. 102 (51): 18676–81. doi:10.1073/pnas.0508052102. PMC 1317945. PMID 16352719.
7. 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.
8. Plowey ED, Cherra SJ, Liu YJ, Chu CT (May 2008). "Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells". J. Neurochem. 105 (3): 1048–56. doi:10.1111/j.1471-4159.2008.05217.x. PMC 2361385. PMID 18182054.
9. 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". J. Neurosci. 32 (22): 7585–93. doi:10.1523/JNEUROSCI.5809-11.2012. PMC 3382107. PMID 22649237.
10. 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". Hum. Mol. Genet. 21 (3): 511–25. doi:10.1093/hmg/ddr481. PMC 3259011. PMID 22012985.
11. 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 (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. doi:10.1371/journal.pone.0018568. PMC 3071839. PMID 21494637.
12. 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". Hum. Mol. Genet. 18 (21): 4022–34. doi:10.1093/hmg/ddp346. PMC 2758136. PMID 19640926.
13. Cherra SJ, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT (August 2010). "Regulation of the autophagy protein LC3 by phosphorylation". J. Cell Biol. 190 (4): 533–9. doi:10.1083/jcb.201002108. PMC 2928022. PMID 20713600.
14. Cherra SJ, Steer E, Gusdon AM, Kiselyov K, Chu CT (February 2013). "Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons". Am. J. Pathol. 182 (2): 474–84. doi:10.1016/j.ajpath.2012.10.027. PMC 3562730. PMID 23231918.
15. 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 (March 2013). "Interplay of LRRK2 with chaperone-mediated autophagy". Nat. Neurosci. 16 (4): 394–406. doi:10.1038/nn.3350. PMID 23455607.
16. "Entrez Gene: LRRK2 leucine-rich repeat kinase 2".
17. 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". The Lancet. 365 (9457): 415–6. doi:10.1016/S0140-6736(05)17830-1. PMID 15680457.
18. Manolio TA (July 2010). "Genomewide association studies and assessment of the risk of disease". N. Engl. J. Med. 363 (2): 166–76. doi:10.1056/NEJMra0905980. PMID 20647212.
19. 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.

Further reading

• Singleton AB (2005). "Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin". Trends Neurosci. 28 (8): 416–21. doi:10.1016/j.tins.2005.05.009. PMID 15955578.
• Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA (2006). "LRRK2 in Parkinson's disease: protein domains and functional insights". Trends Neurosci. 29 (5): 286–93. doi:10.1016/j.tins.2006.03.006. PMID 16616379.
• Haugarvoll K, Wszolek ZK (2006). "PARK8 LRRK2 parkinsonism". Current neurology and neuroscience reports. 6 (4): 287–94. doi:10.1007/s11910-006-0020-0. PMID 16822348.
• Bonifati V (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 (2006). "The importance of LRRK2 mutations in Parkinson disease". Arch. Neurol. 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". J. Neural Transm. Suppl. Journal of Neural Transmission. Supplementa. 70 (70): 221–9. 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". J. Neural Transm. Suppl. Journal of Neural Transmission. Supplementa. 70 (70): 231–4. doi:10.1007/978-3-211-45295-0_35. ISBN 978-3-211-28927-3. PMID 17017534.
• Tan EK (2007). "Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease". Ann. Acad. Med. Singap. 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)