LRRK2

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Leucine-rich repeat kinase 2
Protein LRRK2 PDB 2ZEJ.png
Rendering based on PDB 2ZEJ.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols LRRK2 ; AURA17; DARDARIN; PARK8; RIPK7; ROCO2
External IDs OMIM609007 MGI1913975 HomoloGene18982 ChEMBL: 1075104 GeneCards: LRRK2 Gene
EC number 2.7.11.1
RNA expression pattern
PBB GE LRRK2 gnf1h07577 s at tn.png
PBB GE LRRK2 gnf1h07580 s at tn.png
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 NP_080006
Location (UCSC) Chr 12:
40.59 – 40.76 Mb
Chr 15:
91.67 – 91.82 Mb
PubMed search [1] [2]

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[edit]

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[edit]

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]

References[edit]

  1. ^ a b 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". Proc. Natl. Acad. Sci. U.S.A. 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". J. Neurochem. 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". J. Neurosci. 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". Hum. Mol. Genet. 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 (2011). Cai, Huaibin, 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". Hum. Mol. Genet. 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". J. Cell Biol. 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". Am. J. Pathol. 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 (March 2013). "Interplay of LRRK2 with chaperone-mediated autophagy". Nat. Neurosci. 16 (4): 394–406. doi:10.1038/nn.3350. 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". The 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". N. Engl. J. Med. 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. 

Further reading[edit]

External links[edit]