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Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.

Publication ,  Journal Article
West, AB; Moore, DJ; Choi, C; Andrabi, SA; Li, X; Dikeman, D; Biskup, S; Zhang, Z; Lim, K-L; Dawson, VL; Dawson, TM
Published in: Hum Mol Genet
January 15, 2007

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.

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Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

January 15, 2007

Volume

16

Issue

2

Start / End Page

223 / 232

Location

England

Related Subject Headings

  • Protein Serine-Threonine Kinases
  • Parkinson Disease
  • Neurons
  • Nerve Degeneration
  • Mutation
  • Mice
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Genetics & Heredity
  • GTP Phosphohydrolases
 

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West, A. B., Moore, D. J., Choi, C., Andrabi, S. A., Li, X., Dikeman, D., … Dawson, T. M. (2007). Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet, 16(2), 223–232. https://doi.org/10.1093/hmg/ddl471
West, Andrew B., Darren J. Moore, Catherine Choi, Shaida A. Andrabi, Xiaojie Li, Dustin Dikeman, Saskia Biskup, et al. “Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.Hum Mol Genet 16, no. 2 (January 15, 2007): 223–32. https://doi.org/10.1093/hmg/ddl471.
West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, et al. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet. 2007 Jan 15;16(2):223–32.
West, Andrew B., et al. “Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity.Hum Mol Genet, vol. 16, no. 2, Jan. 2007, pp. 223–32. Pubmed, doi:10.1093/hmg/ddl471.
West AB, Moore DJ, Choi C, Andrabi SA, Li X, Dikeman D, Biskup S, Zhang Z, Lim K-L, Dawson VL, Dawson TM. Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity. Hum Mol Genet. 2007 Jan 15;16(2):223–232.
Journal cover image

Published In

Hum Mol Genet

DOI

ISSN

0964-6906

Publication Date

January 15, 2007

Volume

16

Issue

2

Start / End Page

223 / 232

Location

England

Related Subject Headings

  • Protein Serine-Threonine Kinases
  • Parkinson Disease
  • Neurons
  • Nerve Degeneration
  • Mutation
  • Mice
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Humans
  • Genetics & Heredity
  • GTP Phosphohydrolases