| Identifikační kód |
RIV/00216224:14310/17:00094936 |
| Název v anglickém jazyce |
A proteomic analysis of LRRK2 binding partners reveals interactions with multiple signaling components of the WNT/PCP pathway |
| Druh |
J - Recenzovaný odborný článek (Jimp, Jsc a Jost) |
| Poddruh |
J/A - Článek v odborném periodiku je obsažen v databázi Web of Science společností Thomson Reuters s příznakem „Article“, „Review“ nebo „Letter“ (Jimp) |
| Jazyk |
eng - angličtina |
| Vědní obor |
30210 - Clinical neurology |
| Rok uplatnění |
2017 |
| Kód důvěrnosti údajů |
S - Úplné a pravdivé údaje o výsledku nepodléhající ochraně podle zvláštních právních předpisů. |
| Počet výskytů výsledku |
2 |
| Popis výsledku v anglickém jazyce |
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. |
| Klíčová slova oddělená středníkem |
WNT/planar cell polarity;PRICKLE1;CELSR1;DVL;Parkinson's disease;Dopaminergic neurons;Substantia nigra;Immunoprecipitation;Endocytosis;Signalosomes |
| Stránka www, na které se nachází výsledek |
- |
| DOI výsledku |
10.1186/s13024-017-0193-9 |
| Odkaz na údaje z výzkumu |
- |