Please use this identifier to cite or link to this item: https://doi.org/10.1093/hmg/ddl471
Title: Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity
Authors: West A.B.
Moore D.J.
Choi C.
Andrabi S.A.
Li X.
Dikeman D.
Biskup S.
Zhang Z. 
Lim K.-L. 
Dawson V.L.
Dawson T.M.
Issue Date: 2007
Publisher: Oxford University Press (OUP)
Citation: West A.B., Moore D.J., Choi C., Andrabi S.A., Li X., Dikeman D., Biskup S., Zhang Z., Lim K.-L., Dawson V.L., Dawson T.M. (2007). Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Human Molecular Genetics 16 (2) : 223-232. ScholarBank@NUS Repository. https://doi.org/10.1093/hmg/ddl471
Abstract: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease indistinguishable from idiopathic disease. The mechanisms whereby missense alterations in the LRRK2 gene initiate neurodegeneration remain unknown. Here, we demonstrate that seven of 10 suspected familial-linked mutations result in increased kinase activity. Functional and disease-associated mutations in conserved residues reveal the critical link between intrinsic guanosine triphosphatase (GTPase) activity and downstream kinase activity. LRRK2 kinase activity requires GTPase activity, whereas GTPase activity functions independently of kinase activity. Both LRRK2 kinase and GTPase activity are required for neurotoxicity and potentiate peroxide-induced cell death, although LRRK2 does not function as a canonical MAP-kinase-kinase-kinase. These results suggest a link between LRRK2 kinase activity and pathogenic mechanisms relating to neurodegeneration, further supporting a gain-of-function role for LRRK2 mutations. © 2007 Oxford University Press.
Source Title: Human Molecular Genetics
URI: http://scholarbank.nus.edu.sg/handle/10635/150215
ISSN: 9646906
DOI: 10.1093/hmg/ddl471
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