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{{Infobox_gene}}
{{Infobox_gene}}
'''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]].<ref name="pmid15541308"/> 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]].<ref name="pmid15541308">{{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, Carrera IM, 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 | url =  }}</ref><ref name="pmid15541309">{{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 = 601–7 |date=November 2004 | pmid = 15541309 | doi = 10.1016/j.neuron.2004.11.005 | url =  }}</ref>
'''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]].<ref name="pmid15541308"/> 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]].<ref name="pmid15541308">{{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, Carrera IM, 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 }}</ref><ref name="pmid15541309">{{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 = 601–7 | date = November 2004 | pmid = 15541309 | doi = 10.1016/j.neuron.2004.11.005 }}</ref>


== Function ==
== 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 repeat|WD40]] domain. The protein is present largely in the cytoplasm but also associates with the [[Outer mitochondrial membrane|mitochondrial outer membrane]].
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 repeat|WD40]] domain. The protein is present largely in the cytoplasm but also associates with the [[Outer mitochondrial membrane|mitochondrial outer membrane]].


LRRK2  interacts with the [[C-terminus|C-terminal]] R2 [[RING finger domain]] of [[parkin (ligase)|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.<ref name="pmid16352719">{{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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 102 | issue = 51 | pages = 18676–81 |date=December 2005 | pmid = 16352719 | pmc = 1317945 | doi = 10.1073/pnas.0508052102 | url =  }}</ref>
LRRK2  interacts with the [[C-terminus|C-terminal]] R2 [[RING finger domain]] of [[parkin (ligase)|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.<ref name="pmid16352719">{{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 = 18676–81 | date = December 2005 | pmid = 16352719 | pmc = 1317945 | doi = 10.1073/pnas.0508052102 }}</ref>


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.<ref name="pmid17114044">{{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 = 587–93 |date=November 2006 | pmid = 17114044 | doi = 10.1016/j.neuron.2006.10.008 }}</ref> This is mediated in part by alterations in macroautophagy,<ref name="pmid18182054">{{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 = J. Neurochem. | volume = 105 | issue = 3 | pages = 1048–56 |date=May 2008 | pmid = 18182054 | pmc = 2361385 | doi = 10.1111/j.1471-4159.2008.05217.x }}</ref><ref name="pmid22649237">{{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 = J. Neurosci. | volume = 32 | issue = 22 | pages = 7585–93 |date=May 2012 | pmid = 22649237 | pmc = 3382107 | doi = 10.1523/JNEUROSCI.5809-11.2012 }}</ref><ref name="pmid22012985">{{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 = Hum. Mol. Genet. | volume = 21 | issue = 3 | pages = 511–25 |date=February 2012 | pmid = 22012985 | pmc = 3259011 | doi = 10.1093/hmg/ddr481 }}</ref><ref name="pmid21494637">{{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 | year = 2011 | pmid = 21494637 | pmc = 3071839 | doi = 10.1371/journal.pone.0018568 | editor1-last = Cai | editor1-first = Huaibin }}</ref><ref name="pmid19640926">{{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 = Hum. Mol. Genet. | volume = 18 | issue = 21 | pages = 4022–34 |date=November 2009 | pmid = 19640926 | pmc = 2758136 | doi = 10.1093/hmg/ddp346 }}</ref> and can be prevented by protein kinase A regulation of the autophagy protein LC3.<ref name="pmid20713600">{{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 = J. Cell Biol. | volume = 190 | issue = 4 | pages = 533–9 |date=August 2010 | pmid = 20713600 | pmc = 2928022 | doi = 10.1083/jcb.201002108 }}</ref> The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.<ref name="pmid23231918">{{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 = Am. J. Pathol. | volume = 182 | issue = 2 | pages = 474–84 |date=February 2013 | pmid = 23231918 | pmc = 3562730 | doi = 10.1016/j.ajpath.2012.10.027 }}</ref>  LRRK2 is also a substrate for chaperone-mediated autophagy.<ref name="pmid23455607">{{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 = Nat. Neurosci. | volume = 16| issue = 4| pages = 394–406|date=March 2013 | pmid = 23455607 | doi = 10.1038/nn.3350 | pmc=3609872}}</ref>
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.<ref name="pmid17114044">{{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 = 587–93 | date = November 2006 | pmid = 17114044 | doi = 10.1016/j.neuron.2006.10.008 }}</ref> This is mediated in part by alterations in macroautophagy,<ref name="pmid18182054">{{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 = 1048–56 | date = May 2008 | pmid = 18182054 | pmc = 2361385 | doi = 10.1111/j.1471-4159.2008.05217.x }}</ref><ref name="pmid22649237">{{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 = 7585–93 | date = May 2012 | pmid = 22649237 | pmc = 3382107 | doi = 10.1523/JNEUROSCI.5809-11.2012 }}</ref><ref name="pmid22012985">{{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 = 511–25 | date = February 2012 | pmid = 22012985 | pmc = 3259011 | doi = 10.1093/hmg/ddr481 }}</ref><ref name="pmid21494637">{{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 | editor1-last = Cai | editor1-first = Huaibin }}</ref><ref name="pmid19640926">{{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 = 4022–34 | date = November 2009 | pmid = 19640926 | pmc = 2758136 | doi = 10.1093/hmg/ddp346 }}</ref> and can be prevented by protein kinase A regulation of the autophagy protein LC3.<ref name="pmid20713600">{{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 = 533–9 | date = August 2010 | pmid = 20713600 | pmc = 2928022 | doi = 10.1083/jcb.201002108 }}</ref> The G2019S and R1441C mutations elicit post-synaptic calcium imbalance, leading to excess mitochondrial clearance from dendrites by mitophagy.<ref name="pmid23231918">{{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 = 474–84 | date = February 2013 | pmid = 23231918 | pmc = 3562730 | doi = 10.1016/j.ajpath.2012.10.027 }}</ref>  LRRK2 is also a substrate for chaperone-mediated autophagy.<ref name="pmid23455607">{{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 }}</ref>


== Clinical significance ==
== Clinical significance ==


[[Mutation]]s in this gene have been associated with [[Parkinson's disease]] type 8.<ref>{{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| accessdate = }}</ref>
[[Mutation]]s in this gene have been associated with [[Parkinson's disease]] type 8.<ref>{{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| access-date = }}</ref>


The Gly2019Ser mutation in LRRK2 is a relatively common cause of familial Parkinson's Disease in Caucasians.<ref name="pmid15680457">{{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 = The Lancet | volume = 365 | issue = 9457 | pages = 415–6 |date=February 2005 | pmid = 15680457 | url =  | doi = 10.1016/S0140-6736(05)17830-1 }}</ref> 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 in LRRK2 is a relatively common cause of familial Parkinson's disease in Caucasians.<ref name="pmid15680457">{{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 = 415–6 | date = February 2005 | pmid = 15680457 | doi = 10.1016/S0140-6736(05)17830-1 }}</ref> 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.{{Citation needed|date=April 2014}}
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.{{Citation needed|date=April 2014}}


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.<ref name="Manolio_2010">{{cite journal | author = Manolio TA | title = Genomewide association studies and assessment of the risk of disease | journal = N. Engl. J. Med. | volume = 363 | issue = 2 | pages = 166–76 |date=July 2010 | pmid = 20647212 | doi = 10.1056/NEJMra0905980 | url = }}</ref><ref name="IPDGC_2010">{{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 = 641–9 |date=February 2011 | pmid = 21292315 | doi = 10.1016/S0140-6736(10)62345-8 | pmc=3696507}}</ref>
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.<ref name="Manolio_2010">{{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 = 166–76 | date = July 2010 | pmid = 20647212 | doi = 10.1056/NEJMra0905980 }}</ref><ref name="IPDGC_2010">{{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 = 641–9 | date = February 2011 | pmid = 21292315 | pmc = 3696507 | doi = 10.1016/S0140-6736(10)62345-8 | url = https://archive-ouverte.unige.ch/unige:45211/ATTACHMENT01 }}</ref>


==References==
Attempts have been made to grow crystals of the LRRK2 aboard the [[International Space Station]], as the low-gravity environment renders the crystals less susceptible to sedimentation and convection, and thus easier to map.<ref>{{cite news |publisher=''[[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 |first=Mark |last=Carreau |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}}</ref>
 
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<ref>“Young-Onset Parkinson's.” Parkinson's Foundation, 2 Oct. 2018, www.parkinson.org/Understanding-Parkinsons/What-is-Parkinsons/Young-Onset-Parkinsons.</ref>
 
== References ==
{{reflist}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal | author=Singleton AB |title=Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin |journal=Trends Neurosci. |volume=28 |issue= 8 |pages= 416–21 |year= 2005 |pmid= 15955578 |doi= 10.1016/j.tins.2005.05.009 }}
* {{cite journal | vauthors = Singleton AB | title = Altered alpha-synuclein homeostasis causing Parkinson's disease: the potential roles of dardarin | journal = Trends in Neurosciences | volume = 28 | issue = 8 | pages = 416–21 | date = August 2005 | pmid = 15955578 | doi = 10.1016/j.tins.2005.05.009 }}
*{{cite journal |vauthors=Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA |title=LRRK2 in Parkinson's disease: protein domains and functional insights |journal=Trends Neurosci. |volume=29 |issue= 5 |pages= 286–93 |year= 2006 |pmid= 16616379 |doi= 10.1016/j.tins.2006.03.006 }}
* {{cite journal | vauthors = Mata IF, Wedemeyer WJ, Farrer MJ, Taylor JP, Gallo KA | title = LRRK2 in Parkinson's disease: protein domains and functional insights | journal = Trends in Neurosciences | volume = 29 | issue = 5 | pages = 286–93 | date = May 2006 | pmid = 16616379 | doi = 10.1016/j.tins.2006.03.006 }}
*{{cite journal |vauthors=Haugarvoll K, Wszolek ZK |title=PARK8 LRRK2 parkinsonism |journal=Current Neurology and Neuroscience Reports |volume=6 |issue= 4 |pages= 287–94 |year= 2006 |pmid= 16822348 |doi=10.1007/s11910-006-0020-0 }}
* {{cite journal | vauthors = Haugarvoll K, Wszolek ZK | title = PARK8 LRRK2 parkinsonism | journal = Current Neurology and Neuroscience Reports | volume = 6 | issue = 4 | pages = 287–94 | date = July 2006 | pmid = 16822348 | doi = 10.1007/s11910-006-0020-0 }}
*{{cite journal | author=Bonifati V |title=The pleomorphic pathology of inherited Parkinson's disease: lessons from LRRK2 |journal=Current Neurology and Neuroscience Reports |volume=6 |issue= 5 |pages= 355–7 |year= 2006 |pmid= 16928343 |doi=10.1007/s11910-996-0013-z }}
* {{cite journal | vauthors = Bonifati V | title = The pleomorphic pathology of inherited Parkinson's disease: lessons from LRRK2 | journal = Current Neurology and Neuroscience Reports | volume = 6 | issue = 5 | pages = 355–7 | date = September 2006 | pmid = 16928343 | doi = 10.1007/s11910-996-0013-z }}
*{{cite journal | author=Schapira AH |title=The importance of LRRK2 mutations in Parkinson disease |journal=Arch. Neurol. |volume=63 |issue= 9 |pages= 1225–8 |year= 2006 |pmid= 16966498 |doi= 10.1001/archneur.63.9.1225 }}
* {{cite journal | vauthors = Schapira AH | title = The importance of LRRK2 mutations in Parkinson disease | journal = Archives of Neurology | volume = 63 | issue = 9 | pages = 1225–8 | date = September 2006 | pmid = 16966498 | doi = 10.1001/archneur.63.9.1225 }}
*{{cite journal |vauthors=Whaley NR, Uitti RJ, Dickson DW, Farrer MJ, Wszolek ZK |title=Clinical and pathologic features of families with LRRK2-associated Parkinson's disease |journal=J. Neural Transm. Suppl. |volume= 70|issue= 70 |pages= 221–9 |year= 2006 |pmid= 17017533 |doi=10.1007/978-3-211-45295-0_34 | series=Journal of Neural Transmission. Supplementa  | isbn=978-3-211-28927-3 }}
* {{cite journal | vauthors = Whaley NR, Uitti RJ, Dickson DW, Farrer MJ, Wszolek ZK | title = Clinical and pathologic features of families with LRRK2-associated Parkinson's disease | journal = Journal of Neural Transmission. Supplementum | volume = 70 | issue = 70 | pages = 221–9 | year = 2006 | pmid = 17017533 | doi = 10.1007/978-3-211-45295-0_34 | isbn = 978-3-211-28927-3 | series = Journal of Neural Transmission. Supplementa }}
*{{cite journal | author=Gasser T |title=Molecular genetic findings in LRRK2 American, Canadian and German families |journal=J. Neural Transm. Suppl. |volume= 70|issue= 70 |pages= 231–4 |year= 2006 |pmid= 17017534 |doi=10.1007/978-3-211-45295-0_35 | series=Journal of Neural Transmission. Supplementa  | isbn=978-3-211-28927-3 }}
* {{cite journal | vauthors = Gasser T | title = Molecular genetic findings in LRRK2 American, Canadian and German families | journal = Journal of Neural Transmission. Supplementum | volume = 70 | issue = 70 | pages = 231–4 | year = 2006 | pmid = 17017534 | doi = 10.1007/978-3-211-45295-0_35 | isbn = 978-3-211-28927-3 | series = Journal of Neural Transmission. Supplementa }}
*{{cite journal | author=Tan EK |title=Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease |journal=Ann. Acad. Med. Singap. |volume=35 |issue= 11 |pages= 840–2 |year= 2007 |pmid= 17160203 |doi=  }}
* {{cite journal | vauthors = Tan EK | title = Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease | journal = Annals of the Academy of Medicine, Singapore | volume = 35 | issue = 11 | pages = 840–2 | date = November 2006 | pmid = 17160203 | doi =  }}
{{refend}}
{{refend}}


==External links==
== 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]
*[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}}
* {{MeshName|LRRK2+protein,+human}}

Latest revision as of 15:28, 8 December 2018

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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.[1] 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.[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]

The Gly2019Ser mutation in LRRK2 is a relatively common cause of familial Parkinson's disease in Caucasians.[14] 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.[citation needed]

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.[15][16]

Attempts have been made to grow crystals of the LRRK2 aboard the International Space Station, as the low-gravity environment renders the crystals less susceptible to sedimentation and convection, and thus easier to map.[17]

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[18]

References

  1. ↑ 1.0 1.1 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 (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.
  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 (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.
  3. ↑ 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. doi:10.1073/pnas.0508052102. PMC 1317945. PMID 16352719.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ 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.
  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 (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. doi:10.1371/journal.pone.0018568. PMC 3071839. PMID 21494637.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  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 (April 2013). "Interplay of LRRK2 with chaperone-mediated autophagy". Nature Neuroscience. 16 (4): 394–406. doi:10.1038/nn.3350. PMC 3609872. PMID 23455607.
  13. ↑ "Entrez Gene: LRRK2 leucine-rich repeat kinase 2".
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ “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". Journal of Neural Transmission. Supplementum. 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". Journal of Neural Transmission. Supplementum. 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 (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

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