LRRK2 functions as a Wnt signaling scaffold, bridging cytosolic proteins and membrane-localized LRP6

Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, United Kingdom.
Human Molecular Genetics (Impact Factor: 6.39). 08/2012; 21(22):4966-79. DOI: 10.1093/hmg/dds342
Source: PubMed


Mutations in PARK8, encoding leucine-rich repeat kinase 2 (LRRK2), are a frequent cause of Parkinson's disease (PD). Nonetheless, the physiological role of LRRK2 remains unclear. Here, we demonstrate that LRRK2 participates in canonical Wnt signaling as a scaffold. LRRK2 interacts with key Wnt signaling proteins of the β-catenin destruction complex and dishevelled proteins in vivo and is recruited to membranes following Wnt stimulation, where it binds to the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) in cellular models. LRRK2, therefore, bridges membrane and cytosolic components of Wnt signaling. Changes in LRRK2 expression affects pathway activity, while pathogenic LRRK2 mutants reduce both signal strength and the LRRK2-LRP6 interaction. Thus, decreased LRRK2-mediated Wnt signaling caused by reduced binding to LRP6 may underlie the neurodegeneration observed in PD. Finally, a newly developed LRRK2 kinase inhibitor disrupted Wnt signaling to a similar extent as pathogenic LRRK2 mutations. The use of LRRK2 kinase inhibition to treat PD may therefore need reconsideration.

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Available from: Daniel C Berwick, Mar 12, 2014
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    • "Interestingly, links between pathogenic LRRK2 and abnormal Wnt signalling pathways have recently emerged (reviewed in Berwick and Harvey, 2012b). Whilst this has been shown to involve an altered scaffolding of cytosolic and membrane components required for proper Wnt signalling at the level of the receptor (Berwick and Harvey, 2012a), it will be interesting to see whether pathogenic LRRK2 causes additional deficits in Wnt signalling due to altered Wnt secretion in a retromermediated manner. These findings are somewhat in contrast to recent studies indicating that LRRK2 forms a complex with rab7L1 to promote clearance of trans-Golgi-derived vesicles through the autophagylysosomal system (Beilina et al., 2014). "
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    ABSTRACT: Mutations in LRRK2 (leucine-rich repeat kinase 2) are found associated with both sporadic and familial Parkinson´s disease (PD). Pathogenic mutations are localized to the catalytic domains of LRRK2, including kinase and GTPase domains. Altered catalytic activity correlates with neurotoxicity, indicating that targeting those activities may provide clues as to novel therapeutic strategies for LRRK2-linked PD. However, the cellular readout of such altered catalytic activities remains largely unknown. Recent cell biological studies have started to highlight possible early cellular events which are altered in the presence of pathogenic LRRK2 and may ultimately lead to neuronal demise, and these studies link altered LRRK2 function to various abnormal endolysosomal vesicular trafficking events. This review examines our current knowledge of LRRK2 neurobiology and how pathogenic mutations may lead to neurodegeneration in PD.
    Neuropharmacology 05/2014; 85. DOI:10.1016/j.neuropharm.2014.05.020 · 5.11 Impact Factor
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    • "Mutations in LRRK2 have been found to be the most frequent cause of late onsets PD and are found in both hereditary and sporadic forms of PD (Paisán-Ruíz et al., 2004; Zimprich et al., 2004; Bekris et al., 2010). LRRK2 has been linked to a multitude of cellular functions and pathways, including regulation of neurite outgrowth, Wnt signaling, mitochondrial disease, and autophagy (Dächsel et al., 2010; Winner et al., 2011; Berwick and Harvey, 2012; Papkovskaia et al., 2012). Several studies have identified interaction partners of LRRK2, including 14-3-3, Tubulin, ArfGAP1, Rac1, and DVL (Sancho et al., 2009; Chan et al., 2011; Kawakami et al., 2012; Xiong et al., 2012; Dzamko et al., 2013; Fraser et al., 2013). "
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    ABSTRACT: Human leucine rich repeat kinase 2 (LRRK2) belongs to the Roco family of proteins, which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), and a kinase domain. Mutations in LRRK2 have been found to be thus far the most frequent cause of late-onset Parkinson's disease (PD). Several of the pathogenic mutations in LRRK2 result in decreased GTPase activity and enhanced kinase activity, suggesting a possible PD-related gain of abnormal function. Important progress in the structural understanding of LRRK2 has come from our work with related Roco proteins from lower organisms. Atomic structures of Roco proteins from prokaryotes revealed that Roco proteins belong to the GAD class of molecular switches (G proteins activated by nucleotide dependent dimerization). As in LRRK2, PD-analogous mutations in Roco proteins from bacteria decrease the GTPase reaction. Studies with Roco proteins from the model organism Dictyostelium discoideum revealed that PD mutants have different effects and most importantly they explained the G2019S-related increased LRRK2 kinase activity. Furthermore, the structure of Dictyostelium Roco4 kinase in complex with the LRRK2 inhibitor H1152 showed that Roco4 and other Roco family proteins can be important for the optimization of the current, and identification of new, LRRK2 kinase inhibitors. In this review we highlight the recent progress in structural and biochemical characterization of Roco proteins and discuss its implication for the understanding of the complex regulatory mechanism of LRRK2.
    Frontiers in Molecular Neuroscience 05/2014; 7:32. DOI:10.3389/fnmol.2014.00032 · 4.08 Impact Factor
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    • "c o m / l o c a t e / y n b d i to LRRK2. A wide range of putative phosphorylation targets and interacting proteins for LRRK2 have been proposed, including α-synuclein, 4E-BP1, moesin, tubulin, dvl, lrp6 and ArfGAP1 (Berwick and Harvey, 2012; Gandhi et al., 2008; Imai et al., 2008; Jaleel et al., 2007; Qing et al., 2009; Sancho et al., 2009; Stafa et al., 2012). The physiological relevance of the majority of these interactions are yet to be determined whilst some may have limited implications in vivo (Trancikova et al., 2012). "
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    ABSTRACT: Mutations in LRRK2 are the most common genetic cause of Parkinson's disease (PD). The most prevalent LRRK2 mutation is the G2019S coding change, located in the kinase domain of this complex multi-domain protein. The majority of G2019S autopsy cases feature typical Lewy Body pathology with a clinical phenotype almost indistinguishable from idiopathic PD (iPD). Here we have investigated the biochemical characteristics of α-synuclein in G2019S LRRK2 PD post-mortem material, in comparison to pathology-matched iPD. Immunohistochemistry with pS129 α-synuclein antibody showed that the medulla is heavily affected with pathology in G2019S PD whilst the basal ganglia (BG), limbic and frontal cortical regions demonstrated comparable pathology scores between G2019S PD and iPD. Significantly lower levels of the highly aggregated α-synuclein species in urea-SDS fractions were observed in G2019S cases compared to iPD in BG and limbic cortex. Our data, albeit from a small number of cases, highlight a difference in the biochemical properties of aggregated α-synuclein in G2019S linked PD compared to iPD, despite a similar histopathological presentation. This divergence in solubility is most notable in the basal ganglia, a region that is affected preclinically and is damaged before overt dopaminergic cell death.
    Neurobiology of Disease 06/2013; 58(100). DOI:10.1016/j.nbd.2013.05.017 · 5.08 Impact Factor
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