LRRK2 explained

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.[1] [2]

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.[3]

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.[4] This is mediated in part by alterations in macroautophagy,[5] [6] [7] [8] [9] and can be prevented by protein kinase A regulation of the autophagy protein LC3.[10] The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.[11] LRRK2 is also a substrate for chaperone-mediated autophagy.[12]

Clinical significance

Mutations in this gene have been associated with Parkinson's disease type 8.[13] [14]

The Gly2019Ser mutation results in enhanced kinase activity, and is a relatively common cause of familial Parkinson's disease in Caucasians.[15] 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.[16] [17]

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]

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.[20]

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.[21]

Further reading

External links

Notes and References

  1. 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 . Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease . Neuron . 44 . 4 . 595–600 . November 2004 . 15541308 . 10.1016/j.neuron.2004.10.023 . 16688488 . free .
  2. 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 . Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology . Neuron . 44 . 4 . 601–7 . November 2004 . 15541309 . 10.1016/j.neuron.2004.11.005 . 8642468 . free .
  3. Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA . 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 . December 2005 . 16352719 . 1317945 . 10.1073/pnas.0508052102 . 2005PNAS..10218676S . free .
  4. MacLeod D, Dowman J, Hammond R, Leete T, Inoue K, Abeliovich A . The familial Parkinsonism gene LRRK2 regulates neurite process morphology . Neuron . 52 . 4 . 587–93 . November 2006 . 17114044 . 10.1016/j.neuron.2006.10.008 . 16966163 . free .
  5. Plowey ED, Cherra SJ, Liu YJ, Chu CT . Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells . Journal of Neurochemistry . 105 . 3 . 1048–56 . May 2008 . 18182054 . 2361385 . 10.1111/j.1471-4159.2008.05217.x .
  6. Friedman LG, Lachenmayer ML, Wang J, He L, Poulose SM, Komatsu M, Holstein GR, Yue Z . 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 . May 2012 . 22649237 . 3382107 . 10.1523/JNEUROSCI.5809-11.2012 .
  7. Gómez-Suaga P, Luzón-Toro B, Churamani D, Zhang L, Bloor-Young D, Patel S, Woodman PG, Churchill GC, Hilfiker S . Leucine-rich repeat kinase 2 regulates autophagy through a calcium-dependent pathway involving NAADP . Human Molecular Genetics . 21 . 3 . 511–25 . February 2012 . 22012985 . 3259011 . 10.1093/hmg/ddr481 .
  8. 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 . Dopaminergic neuronal loss, reduced neurite complexity and autophagic abnormalities in transgenic mice expressing G2019S mutant LRRK2 . PLOS ONE . 6 . 4 . e18568 . April 2011 . 21494637 . 3071839 . 10.1371/journal.pone.0018568 . Cai . Huaibin . 2011PLoSO...618568R . free .
  9. Alegre-Abarrategui J, Christian H, Lufino MM, Mutihac R, Venda LL, Ansorge O, Wade-Martins R . 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 . November 2009 . 19640926 . 2758136 . 10.1093/hmg/ddp346 .
  10. Cherra SJ, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT . Regulation of the autophagy protein LC3 by phosphorylation . The Journal of Cell Biology . 190 . 4 . 533–9 . August 2010 . 20713600 . 2928022 . 10.1083/jcb.201002108 .
  11. Cherra SJ, Steer E, Gusdon AM, Kiselyov K, Chu CT . Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons . The American Journal of Pathology . 182 . 2 . 474–84 . February 2013 . 23231918 . 3562730 . 10.1016/j.ajpath.2012.10.027 .
  12. 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 . Interplay of LRRK2 with chaperone-mediated autophagy . Nature Neuroscience . 16 . 4 . 394–406 . April 2013 . 23455607 . 3609872 . 10.1038/nn.3350 .
  13. Web site: Entrez Gene: LRRK2 leucine-rich repeat kinase 2.
  14. Web site: PhD . Lindsey Shapiro . 2023-09-18 . Researchers win Breakthrough Prize for Parkinson's genetics discoveries Parkinson's News Today . 2023-09-20 . parkinsonsnewstoday.com . en-US.
  15. 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 . A common LRRK2 mutation in idiopathic Parkinson's disease . Lancet . 365 . 9457 . 415–6 . February 2005 . 15680457 . 10.1016/S0140-6736(05)17830-1 . 36186136 .
  16. 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 . 6 . Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study . The Lancet. Neurology . 7 . 7 . 583–90 . July 2008 . 18539534 . 2832754 . 10.1016/S1474-4422(08)70117-0 .
  17. Lesage S, Dürr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, Pollak P, Brice A . 6 . LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs . The New England Journal of Medicine . 354 . 4 . 422–3 . January 2006 . 16436781 . 10.1056/NEJMc055540 . free .
  18. Manolio TA . Genomewide association studies and assessment of the risk of disease . The New England Journal of Medicine . 363 . 2 . 166–76 . July 2010 . 20647212 . 10.1056/NEJMra0905980 . free .
  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 . 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 . February 2011 . 21292315 . 3696507 . 10.1016/S0140-6736(10)62345-8 .
  20. . 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. . ISS Cargo Missions To Test Soyuz, Deliver New Science . Mark . Carreau . November 14, 2018 .
  21. “Young-Onset Parkinson's.” Parkinson's Foundation, 2 Oct. 2018, www.parkinson.org/Understanding-Parkinsons/What-is-Parkinsons/Young-Onset-Parkinsons.

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