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A QUICK screen for Lrrk2 interaction partners: leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics

Andrea Meixner, Karsten Boldt, Marleen Van Troys UGent, Manor Askenazi, Chrsitian J Gloeckner, Matthias Bauer, Jarrod A Marto, Christophe Ampe UGent, Norbert Kinkl and Marius Ueffing (2011) MOLECULAR & CELLULAR PROTEOMICS. 10(1).
abstract
Mutations in human leucine-rich repeat kinase 2 (Lrrk2), a protein of yet unknown function, are linked to Parkinson's disease caused by degeneration of midbrain dopaminergic neurons. The protein comprises several domains including a GTPase and a kinase domain both affected by several pathogenic mutations. To elucidate the molecular interaction network of endogenous Lrrk2 under stoichiometric constraints, we applied QUICK (quantitative immunoprecipitation combined with knockdown) in NIH3T3 cells. The identified interactome reveals actin isoforms as well as actin-associated proteins involved in actin filament assembly, organization, rearrangement, and maintenance, suggesting that the biological function of Lrrk2 is linked to cytoskeletal dynamics. In fact, we demonstrate Lrrk2 de novo binding to F-actin and its ability to modulate its assembly in vitro. When tested in intact cells, knockdown of Lrrk2 causes morphological alterations in NIH3T3 cells. In developing dopaminergic midbrain primary neurons, Lrrk2 knockdown results in shortened neurite processes, indicating a physiological role of Lrrk2 in cytoskeletal organization and dynamics of dopaminergic neurons. Hence, our results demonstrate that molecular interactions as well as the physiological function of Lrrk2 are closely related to the organization of the actin-based cytoskeleton, a crucial feature of neuronal development and neuron function.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
NEURONAL MORPHOGENESIS, DOPAMINERGIC-NEURONS, RNA INTERFERENCE, BINDING PROTEINS, GENE-EXPRESSION, MOUSE-BRAIN, ROC DOMAIN, CROSS-LINKING, AUTOSOMAL-DOMINANT PARKINSONISM, DISEASE-ASSOCIATED MUTATIONS
journal title
MOLECULAR & CELLULAR PROTEOMICS
Mol. Cell. Proteomics
volume
10
issue
1
pages
17 pages
Web of Science type
Article
Web of Science id
000286928400006
JCR category
BIOCHEMICAL RESEARCH METHODS
JCR impact factor
7.398 (2011)
JCR rank
5/72 (2011)
JCR quartile
1 (2011)
ISSN
1535-9476
DOI
10.1074/mcp.M110.001172
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1197816
handle
http://hdl.handle.net/1854/LU-1197816
date created
2011-03-28 11:25:54
date last changed
2013-01-30 09:41:15
@article{1197816,
  abstract     = {Mutations in human leucine-rich repeat kinase 2 (Lrrk2), a protein of yet unknown function, are linked to Parkinson's disease caused by degeneration of midbrain dopaminergic neurons. The protein comprises several domains including a GTPase and a kinase domain both affected by several pathogenic mutations. To elucidate the molecular interaction network of endogenous Lrrk2 under stoichiometric constraints, we applied QUICK (quantitative immunoprecipitation combined with knockdown) in NIH3T3 cells. The identified interactome reveals actin isoforms as well as actin-associated proteins involved in actin filament assembly, organization, rearrangement, and maintenance, suggesting that the biological function of Lrrk2 is linked to cytoskeletal dynamics. In fact, we demonstrate Lrrk2 de novo binding to F-actin and its ability to modulate its assembly in vitro. When tested in intact cells, knockdown of Lrrk2 causes morphological alterations in NIH3T3 cells. In developing dopaminergic midbrain primary neurons, Lrrk2 knockdown results in shortened neurite processes, indicating a physiological role of Lrrk2 in cytoskeletal organization and dynamics of dopaminergic neurons. Hence, our results demonstrate that molecular interactions as well as the physiological function of Lrrk2 are closely related to the organization of the actin-based cytoskeleton, a crucial feature of neuronal development and neuron function.},
  author       = {Meixner, Andrea and Boldt, Karsten and Van Troys, Marleen and Askenazi, Manor and Gloeckner, Chrsitian J and Bauer, Matthias and Marto, Jarrod A and Ampe, Christophe and Kinkl, Norbert and Ueffing, Marius},
  issn         = {1535-9476},
  journal      = {MOLECULAR \& CELLULAR PROTEOMICS},
  keyword      = {NEURONAL MORPHOGENESIS,DOPAMINERGIC-NEURONS,RNA INTERFERENCE,BINDING PROTEINS,GENE-EXPRESSION,MOUSE-BRAIN,ROC DOMAIN,CROSS-LINKING,AUTOSOMAL-DOMINANT PARKINSONISM,DISEASE-ASSOCIATED MUTATIONS},
  language     = {eng},
  number       = {1},
  pages        = {17},
  title        = {A QUICK screen for Lrrk2 interaction partners: leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics},
  url          = {http://dx.doi.org/10.1074/mcp.M110.001172},
  volume       = {10},
  year         = {2011},
}

Chicago
Meixner, Andrea, Karsten Boldt, Marleen Van Troys, Manor Askenazi, Chrsitian J Gloeckner, Matthias Bauer, Jarrod A Marto, Christophe Ampe, Norbert Kinkl, and Marius Ueffing. 2011. “A QUICK Screen for Lrrk2 Interaction Partners: Leucine-rich Repeat Kinase 2 Is Involved in Actin Cytoskeleton Dynamics.” Molecular & Cellular Proteomics 10 (1).
APA
Meixner, A., Boldt, K., Van Troys, M., Askenazi, M., Gloeckner, C. J., Bauer, M., Marto, J. A., et al. (2011). A QUICK screen for Lrrk2 interaction partners: leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics. MOLECULAR & CELLULAR PROTEOMICS, 10(1).
Vancouver
1.
Meixner A, Boldt K, Van Troys M, Askenazi M, Gloeckner CJ, Bauer M, et al. A QUICK screen for Lrrk2 interaction partners: leucine-rich repeat kinase 2 is involved in actin cytoskeleton dynamics. MOLECULAR & CELLULAR PROTEOMICS. 2011;10(1).
MLA
Meixner, Andrea, Karsten Boldt, Marleen Van Troys, et al. “A QUICK Screen for Lrrk2 Interaction Partners: Leucine-rich Repeat Kinase 2 Is Involved in Actin Cytoskeleton Dynamics.” MOLECULAR & CELLULAR PROTEOMICS 10.1 (2011): n. pag. Print.