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@article{1389342,
author = {Salašová, Alena and Yokota, C. and Potěšil, David and Zdráhal, Zbyněk and Bryja, Vítězslav and Arenas, E.},
article_location = {LONDON},
article_number = {54},
doi = {http://dx.doi.org/10.1186/s13024-017-0193-9},
keywords = {WNT/planar cell polarity; PRICKLE1; CELSR1; DVL; Parkinson's disease; Dopaminergic neurons; Substantia nigra; Immunoprecipitation; Endocytosis; Signalosomes},
language = {eng},
issn = {1750-1326},
journal = {MOLECULAR NEURODEGENERATION},
title = {A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway},
volume = {12},
year = {2017}
}
TY - JOUR
ID - 1389342
AU - Salašová, Alena - Yokota, C. - Potěšil, David - Zdráhal, Zbyněk - Bryja, Vítězslav - Arenas, E.
PY - 2017
TI - A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway
JF - MOLECULAR NEURODEGENERATION
VL - 12
IS - 54
SP - 1-19
EP - 1-19
PB - BIOMED CENTRAL LTD
SN - 17501326
KW - WNT/planar cell polarity
KW - PRICKLE1
KW - CELSR1
KW - DVL
KW - Parkinson's disease
KW - Dopaminergic neurons
KW - Substantia nigra
KW - Immunoprecipitation
KW - Endocytosis
KW - Signalosomes
N2 - Background: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/beta-catenin signaling via its interaction with the beta-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients. Methods: Co-immunoprecipitation and tandem mass spectrometry was performed in a mouse substantia nigra cell line (SN4741) and human HEK293T cell line in order to identify novel LRRK2 binding partners. Inhibition of the WNT/beta-catenin reporter, TOPFlash, was used as a read-out of WNT/PCP pathway activation. The capacity of LRRK2 to regulate WNT/PCP signaling in vivo was tested in Xenopus laevis' early development. Results: Our proteomic analysis identified that LRRK2 interacts with proteins involved in WNT/PCP signaling such as the PDZ domain-containing protein GIPC1 and Integrin-linked kinase (ILK) in dopaminergic cells in vitro and in the mouse ventral midbrain in vivo. Moreover, co-immunoprecipitation analysis revealed that LRRK2 binds to two core components of the WNT/PCP signaling pathway, PRICKLE1 and CELSR1, as well as to FLOTILLIN-2 and CULLIN-3, which regulate WNT secretion and inhibit WNT/beta-catenin signaling, respectively. We also found that PRICKLE1 and LRRK2 localize in signalosomes and act as dual regulators of WNT/PCP and beta-catenin signaling. Accordingly, analysis of the function of LRRK2 in vivo, in X. laevis revelaed that LRKK2 not only inhibits WNT/beta-catenin pathway, but induces a classical WNT/PCP phenotype in vivo.
ER -
SALAŠOVÁ, Alena, C. YOKOTA, David POTĚŠIL, Zbyněk ZDRÁHAL, Vítězslav BRYJA and E. ARENAS. A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway. \textit{MOLECULAR NEURODEGENERATION}. LONDON: BIOMED CENTRAL LTD, 2017, vol.~12, No~54, p.~1-19. ISSN~1750-1326. Available from: https://dx.doi.org/10.1186/s13024-017-0193-9.
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