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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 PARK8gene.[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]
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]
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
↑ 1.01.1Paisán-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. PMID15541308.
↑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. PMID15541309.
↑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. PMID15680457.
↑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. PMID20647212.
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. PMID15955578.
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. PMID16616379.
Haugarvoll K, Wszolek ZK (2006). "PARK8 LRRK2 parkinsonism". Current Neurology and Neuroscience Reports. 6 (4): 287–94. doi:10.1007/s11910-006-0020-0. PMID16822348.
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. PMID16928343.
Tan EK (2007). "Identification of a common genetic risk variant (LRRK2 Gly2385Arg) in Parkinson's disease". Ann. Acad. Med. Singap. 35 (11): 840–2. PMID17160203.