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 large, multifunctional kinase enzyme that in humans is encoded by the LRRK2 gene. 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.{{cite journal | vauthors = 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, Martí Carrera I, Pena AS, de Silva R, Lees A, Martí-Massó JF, Pérez-Tur J, Wood NW, Singleton AB | title = Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease | journal = Neuron | volume = 44 | issue = 4 | pages = 595–600 | date = November 2004 | pmid = 15541308 | doi = 10.1016/j.neuron.2004.10.023 | s2cid = 16688488 | doi-access = free }}{{cite journal | vauthors = 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 | title = Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology | journal = Neuron | volume = 44 | issue = 4 | pages = 601–607 | date = November 2004 | pmid = 15541309 | doi = 10.1016/j.neuron.2004.11.005 | s2cid = 8642468 | doi-access = free }}

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.{{cite journal | vauthors = Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA | title = Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 51 | pages = 18676–18681 | date = December 2005 | pmid = 16352719 | pmc = 1317945 | doi = 10.1073/pnas.0508052102 | doi-access = free | bibcode = 2005PNAS..10218676S }}

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.{{cite journal | vauthors = MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A | title = The familial Parkinsonism gene LRRK2 regulates neurite process morphology | journal = Neuron | volume = 52 | issue = 4 | pages = 587–593 | date = November 2006 | pmid = 17114044 | doi = 10.1016/j.neuron.2006.10.008 | s2cid = 16966163 | doi-access = free }} This is mediated in part by alterations in macroautophagy,{{cite journal | vauthors = Plowey ED, Cherra SJ, Liu YJ, Chu CT | title = Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells | journal = Journal of Neurochemistry | volume = 105 | issue = 3 | pages = 1048–1056 | date = May 2008 | pmid = 18182054 | pmc = 2361385 | doi = 10.1111/j.1471-4159.2008.05217.x }}{{cite journal | vauthors = Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z | title = Disrupted autophagy leads to dopaminergic axon and dendrite degeneration and promotes presynaptic accumulation of α-synuclein and LRRK2 in the brain | journal = The Journal of Neuroscience | volume = 32 | issue = 22 | pages = 7585–7593 | date = May 2012 | pmid = 22649237 | pmc = 3382107 | doi = 10.1523/JNEUROSCI.5809-11.2012 }}{{cite journal | vauthors = Gómez-Suaga P, Luzón-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S | title = Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP | journal = Human Molecular Genetics | volume = 21 | issue = 3 | pages = 511–525 | date = February 2012 | pmid = 22012985 | pmc = 3259011 | doi = 10.1093/hmg/ddr481 }}{{cite journal | vauthors = 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 | title = Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2 | journal = PLOS ONE | volume = 6 | issue = 4 | pages = e18568 | date = April 2011 | pmid = 21494637 | pmc = 3071839 | doi = 10.1371/journal.pone.0018568 | veditors = Cai H | doi-access = free | bibcode = 2011PLoSO...618568R }}{{cite journal | vauthors = Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R | title = LRRK2 regulates autophagic activity and localizes to specific membrane microdomains in a novel human genomic reporter cellular model | journal = Human Molecular Genetics | volume = 18 | issue = 21 | pages = 4022–4034 | date = November 2009 | pmid = 19640926 | pmc = 2758136 | doi = 10.1093/hmg/ddp346 }} and can be prevented by protein kinase A regulation of the autophagy protein LC3.{{cite journal | vauthors = Cherra SJ, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT | title = Regulation of the autophagy protein LC3 by phosphorylation | journal = The Journal of Cell Biology | volume = 190 | issue = 4 | pages = 533–539 | date = August 2010 | pmid = 20713600 | pmc = 2928022 | doi = 10.1083/jcb.201002108 }} The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.{{cite journal | vauthors = Cherra SJ, Steer E, Gusdon AM, Kiselyov K, Chu CT | title = Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons | journal = The American Journal of Pathology | volume = 182 | issue = 2 | pages = 474–484 | date = February 2013 | pmid = 23231918 | pmc = 3562730 | doi = 10.1016/j.ajpath.2012.10.027 }} LRRK2 is also a substrate for chaperone-mediated autophagy.{{cite journal | vauthors = 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 | title = Interplay of LRRK2 with chaperone-mediated autophagy | journal = Nature Neuroscience | volume = 16 | issue = 4 | pages = 394–406 | date = April 2013 | pmid = 23455607 | pmc = 3609872 | doi = 10.1038/nn.3350 }}

Disease-associated mutant alleles of LRRK2 (R1441C, G2019S, I2020T) generally show elevated kinase activity.{{cite journal | vauthors = West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM | title = Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 46 | pages = 16842–16847 | date = November 2005 | pmid = 16269541 | pmc = 1283829 | doi = 10.1073/pnas.0507360102 | doi-access = free }}{{cite journal | vauthors = Gloeckner CJ, Kinkl N, Schumacher A, Braun RJ, O'Neill E, Meitinger T, Kolch W, Prokisch H, Ueffing M | title = The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity | journal = Human Molecular Genetics | volume = 15 | issue = 2 | pages = 223–232 | date = January 2006 | pmid = 16321986 | doi = 10.1093/hmg/ddi439 }}

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.{{cite journal | vauthors = Keeney MT, Rocha EM, Hoffman EK, Farmer K, Di Maio R, Weir J, Wagner WG, Hu X, Clark CL, Castro SL, Scheirer A, Fazzari M, De Miranda BR, Pintchovski SA, Shrader WD, Pagano PJ, Hastings TG, Greenamyre JT | title = LRRK2 regulates production of reactive oxygen species in cell and animal models of Parkinson's disease | journal = Science Translational Medicine | volume = 16 | issue = 767 | pages = eadl3438 | date = October 2024 | pmid = 39356746 | doi = 10.1126/scitranslmed.adl3438 }}

Clinical significance

Mutations in this gene have been associated with Parkinson's disease type 8.{{cite web | title = Entrez Gene: LRRK2 leucine-rich repeat kinase 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=120892}}{{Cite web | vauthors = Shapiro L |date=2023-09-18 |title=Researchers win Breakthrough Prize for Parkinson's genetics discoveries {{!}} Parkinson's News Today |url=https://parkinsonsnewstoday.com/news/researchers-win-breakthrough-prize-parkinsons-genetics-discoveries/ |access-date=2023-09-20 |website=parkinsonsnewstoday.com |language=en-US}}

The G2019S mutation results in enhanced kinase activity, and is a relatively common cause of familial Parkinson's disease in Caucasians.{{cite journal | vauthors = 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 | title = A common LRRK2 mutation in idiopathic Parkinson's disease | journal = Lancet | volume = 365 | issue = 9457 | pages = 415–416 | date = February 2005 | pmid = 15680457 | doi = 10.1016/S0140-6736(05)17830-1 | s2cid = 36186136 }} 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.{{cite journal | vauthors = Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, Brice A, Aasly J, Zabetian CP, Goldwurm S, Ferreira JJ, Tolosa E, Kay DM, Klein C, Williams DR, Marras C, Lang AE, Wszolek ZK, Berciano J, Schapira AH, Lynch T, Bhatia KP, Gasser T, Lees AJ, Wood NW | title = Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study | journal = The Lancet. Neurology | volume = 7 | issue = 7 | pages = 583–590 | date = July 2008 | pmid = 18539534 | pmc = 2832754 | doi = 10.1016/S1474-4422(08)70117-0 }}{{cite journal | vauthors = Lesage S, Dürr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A | title = LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs | journal = The New England Journal of Medicine | volume = 354 | issue = 4 | pages = 422–423 | date = January 2006 | pmid = 16436781 | doi = 10.1056/NEJMc055540 | doi-access = free }}

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.{{cite journal | vauthors = Manolio TA | title = Genomewide association studies and assessment of the risk of disease | journal = The New England Journal of Medicine | volume = 363 | issue = 2 | pages = 166–176 | date = July 2010 | pmid = 20647212 | doi = 10.1056/NEJMra0905980 | doi-access = free }}{{cite journal | vauthors = 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 | title = Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies | journal = Lancet | volume = 377 | issue = 9766 | pages = 641–649 | date = February 2011 | pmid = 21292315 | pmc = 3696507 | doi = 10.1016/S0140-6736(10)62345-8 }}

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.{{cite magazine |magazine=Aviation Week |quote=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. |title=ISS Cargo Missions To Test Soyuz, Deliver New Science | vauthors = Carreau M |date=November 14, 2018 |url=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}}

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.“Young-Onset Parkinson's.” Parkinson's Foundation, 2 Oct. 2018, www.parkinson.org/Understanding-Parkinsons/What-is-Parkinsons/Young-Onset-Parkinsons.

= Therapeutics development =

Multiple preclinical studies have found that inhibition or silencing of LRRK2 may be therapeutically beneficial for treatment of Parkinson's disease.{{cite journal | vauthors = Daher JP, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB | title = Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 25 | pages = 9289–9294 | date = June 2014 | pmid = 24927544 | pmc = 4078806 | doi = 10.1073/pnas.1403215111 | doi-access = free }}{{cite journal | vauthors = Daher JP, Abdelmotilib HA, Hu X, Volpicelli-Daley LA, Moehle MS, Fraser KB, Needle E, Chen Y, Steyn SJ, Galatsis P, Hirst WD, West AB | title = Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration | journal = The Journal of Biological Chemistry | volume = 290 | issue = 32 | pages = 19433–19444 | date = August 2015 | pmid = 26078453 | pmc = 4528108 | doi = 10.1074/jbc.M115.660001 | doi-access = free }} There have been efforts to develop therapeutics for Parkinson's disease targeting LRRK2, including LRRK2 inhibitors{{cite journal | vauthors = Jennings D, Huntwork-Rodriguez S, Henry AG, Sasaki JC, Meisner R, Diaz D, Solanoy H, Wang X, Negrou E, Bondar VV, Ghosh R, Maloney MT, Propson NE, Zhu Y, Maciuca RD, Harris L, Kay A, LeWitt P, King TA, Kern D, Ellenbogen A, Goodman I, Siderowf A, Aldred J, Omidvar O, Masoud ST, Davis SS, Arguello A, Estrada AA, de Vicente J, Sweeney ZK, Astarita G, Borin MT, Wong BK, Wong H, Nguyen H, Scearce-Levie K, Ho C, Troyer MD | title = Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease | journal = Science Translational Medicine | volume = 14 | issue = 648 | pages = eabj2658 | date = June 2022 | pmid = 35675433 | doi = 10.1126/scitranslmed.abj2658 }}{{cite journal | vauthors = Jennings D, Huntwork-Rodriguez S, Vissers MF, Daryani VM, Diaz D, Goo MS, Chen JJ, Maciuca R, Fraser K, Mabrouk OS, van de Wetering de Rooij J, Heuberger JA, Groeneveld GJ, Borin MT, Cruz-Herranz A, Graham D, Scearce-Levie K, De Vicente J, Henry AG, Chin P, Ho C, Troyer MD | title = LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease | journal = Movement Disorders | volume = 38 | issue = 3 | pages = 386–398 | date = March 2023 | pmid = 36807624 | doi = 10.1002/mds.29297 | hdl = 1887/3748181 | hdl-access = free }} and antisense oligonucleotides (ASOs) targeting LRRK2.{{cite journal | vauthors = Zhao HT, John N, Delic V, Ikeda-Lee K, Kim A, Weihofen A, Swayze EE, Kordasiewicz HB, West AB, Volpicelli-Daley LA | title = LRRK2 Antisense Oligonucleotides Ameliorate α-Synuclein Inclusion Formation in a Parkinson's Disease Mouse Model | journal = Molecular Therapy. Nucleic Acids | volume = 8 | pages = 508–519 | date = September 2017 | pmid = 28918051 | pmc = 5573879 | doi = 10.1016/j.omtn.2017.08.002 }}

References

External links

[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=lrrk2 GeneReviews/NCBI/NIH/UW entry on LRRK2-Related Parkinson Disease]
{{MeshName|LRRK2+protein,+human}}

Category:Parkinson's disease