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Eng-King Tan 1 Article
Leucine-Rich Repeat Kinase 2-Linked Parkinson’s Disease: Clinical and Molecular Findings
Udhaya Kumari, Eng-King Tan
J Mov Disord. 2010;3(2):25-31.
DOI: https://doi.org/10.14802/jmd.10008
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AbstractAbstract PDF

Mutations in Leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of sporadic and familial late onset Parkinson’s disease (PD). The G2019S common mutation has been identified about 1% of sporadic cases and 4–7% of familial cases. Over 50 variants have since been identified in LRRK2, and at least 7 of these are confirmed to be pathogenic. In addition to pathogenic mutations, several common polymorphisms in the LRRK2 gene (G2385R and R1628P) have been identified that may explain up to 10% of sporadic PD in Asian populations. LRRK2 is a large complex multidomain protein with 2,527-amino-acid and the molecular weight is 286 kDa. LRRK2 multidomain protein consists of a catalytic core domain, kinase domain and a number of putative protein-protein interaction domains. LRRK2 mutations found in PD families, including the G2019S and I2020T mutations show increased intrinsic kinase activity, when assessed with myelin basic protein as substrate. The modification of LRRK2 GTPase and kinase activity affecting residues in the ROC, COR and mitogen-activated protein kinase kinase kinases domains is believed to lead to neuronal cell death, but the pathways involved remain unclear. A number of in vivo models in C. elegans, D. melanogaster and mice have been developed to study the patho/physiological function of LRRK2. Based on current literature, a toxic gain of function in LRRK2 kinase activity is a possible pathophysiologic mechanism and thus inhibition of kinase activity in experimental models offers a potential therapeutic strategy for LRRK2-linked PD.

Citations

Citations to this article as recorded by  
  • Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade
    Gunjan Thakur, Vikas Kumar, Keun Woo Lee, Chungkil Won
    Genes.2022; 13(8): 1426.     CrossRef
  • Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis
    George R. Heaton, Natalie Landeck, Adamantios Mamais, Mike A. Nalls, Jonathon Nixon-Abell, Ravindran Kumaran, Alexandra Beilina, Laura Pellegrini, Yan Li, Kirsten Harvey, Mark R. Cookson
    Neurobiology of Disease.2020; 141: 104948.     CrossRef
  • Target Engagement in Lead Generation
    Timothy B. Durham, Maria-Jesus Blanco
    Bioorganic & Medicinal Chemistry Letters.2015;[Epub]     CrossRef

JMD : Journal of Movement Disorders