"LRRK2 is a large protein encompassing several functional domains including a kinase domain with feature similar to mitogen activated protein kinase kinase kinases (MAPKKK) and receptor-interacting protein kinases (RIPK) (Bosgraaf and Van Haastert, 2003; Guo et al., 2006). Several single nucleotide variants have been identified in LRRK2 (Brice, 2005). While only the common G2019S mutation, located in the kinase domain, has been consistently associated with increased kinase activity in vitro (West et al., 2005; Gloeckner et al., 2006; Greggio et al., 2006), a recent study monitoring LRRK2 autophosphorylation at Ser 1292 suggested that other pathogenic mutants possess augmented activity in the cellular context (Sheng et al., 2012). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains executing several functions, including GTP hydrolysis, kinase activity, and protein binding. Robust evidence suggests that LRRK2 acts at the synaptic site as a molecular hub connecting synaptic vesicles to cytoskeletal elements via a complex panel of protein-protein interactions. Here we investigated the impact of pharmacological inhibition of LRRK2 kinase activity on synaptic function. Acute treatment with LRRK2 inhibitors reduced the frequency of spontaneous currents, the rate of synaptic vesicle trafficking and the release of neurotransmitter from isolated synaptosomes. The investigation of complementary models lacking LRRK2 expression allowed us to exclude potential off-side effects of kinase inhibitors on synaptic functions. Next we studied whether kinase inhibition affects LRRK2 heterologous interactions. We found that the binding among LRRK2, presynaptic proteins and synaptic vesicles is affected by kinase inhibition. Our results suggest that LRRK2 kinase activity influences synaptic vesicle release via modulation of LRRK2 macro-molecular complex.
"The precise normal function of the leucine-rich repeat kinase 2 (LRRK2) has yet to be determined, although recent evidence suggests involvement in membrane trafficking (West et al., 2005; Biskup et al., 2006, 2007; Gloeckner et al., 2006; Hatano et al., 2007; Sakaguchi-Nakashima et al., 2007; Alegre-Abarrategui and Wade-Martins, 2009; Alegre-Abarrategui et al., 2009; Lee et al., 2010a,b,c; Tong et al., 2010; Vitte et al., 2010) and cytoskeletal dynamics (Jaleel et al., 2007; Gandhi et al., 2008; Gillardon, 2009; Parisiadou et al., 2009; Lin et al., 2010). Mutations in LRRK2 have been identified as the most common cause of dominantly inherited PD (Brice, 2005; Lesage et al., 2006; Ozelius et al., 2006; Healy et al., 2008) and importantly, variation in the LRRK2 gene has been implicated as a risk factor for sporadic PD (Kett and Dauer, 2012). LRRK2 is thought to contribute to PD pathogenesis through a gain-of-function mechanism (Kett and Dauer, 2012). "
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized primarily by the selective death of dopaminergic (DA) neurons in the substantia nigra pars compacta of the midbrain. Although several genetic forms of PD have been identified, the precise molecular mechanisms underlying DA neuron loss in PD remain elusive. In recent years, microRNAs (miRNAs) have been recognized as potent post-transcriptional regulators of gene expression with fundamental roles in numerous biological processes. Although their role in PD pathogenesis is still a very active area of investigation, several seminal studies have contributed significantly to our understanding of the roles these small non-coding RNAs play in the disease process. Among these are studies which have demonstrated specific miRNAs that target and down-regulate the expression of PD-related genes as well as those demonstrating a reciprocal relationship in which PD-related genes act to regulate miRNA processing machinery. Concurrently, a wealth of knowledge has become available regarding the molecular mechanisms that unify the underlying etiology of genetic and sporadic PD pathogenesis, including dysregulated protein quality control by the ubiquitin-proteasome system and autophagy pathway, activation of programmed cell death, mitochondrial damage and aberrant DA neurodevelopment and maintenance. Following a discussion of the interactions between PD-related genes and miRNAs, this review highlights those studies which have elucidated the roles of these pathways in PD pathogenesis. We highlight the potential of miRNAs to serve a critical regulatory role in the implicated disease pathways, given their capacity to modulate the expression of entire families of related genes. Although few studies have directly linked miRNA regulation of these pathways to PD, a strong foundation for investigation has been laid and this area holds promise to reveal novel therapeutic targets for PD.
"The LRRK2 protein has a molecular weight (MW) of ϳ280 kDa and contains several domains, including a Ras/GTPase like (Roc), a C-terminal of Roc (COR), a kinase (similar to mitogen-activated protein kinase kinase kinases), and a WD40 domain (Bosgraaf and Van Haastert, 2003; Guo et al., 2006). Several single nucleotide alterations have been identified in LRRK2 (Brice, 2005), covering all functional domains, but only five missense mutations clearly segregate with PD in large family studies (Goldwurm et al., 2005; Bonifati, 2006). Some of these mutations cause increased kinase activity (West et al., 2005; Gloeckner et al., 2006, 2009; Greggio et al., 2006). "
[Show abstract][Hide abstract] ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the single most common cause of inherited Parkinson's disease. Little is known about its involvement in the pathogenesis of Parkinson's disease mainly because of the lack of knowledge about the physiological role of LRRK2. To determine the function of LRRK2, we studied the impact of short hairpin RNA-mediated silencing of LRRK2 expression in cortical neurons. Paired recording indicated that LRRK2 silencing affects evoked postsynaptic currents. Furthermore, LRRK2 silencing induces at the presynaptic site a redistribution of vesicles within the bouton, altered recycling dynamics, and increased vesicle kinetics. Accordingly, LRRK2 protein is present in the synaptosomal compartment of cortical neurons in which it interacts with several proteins involved in vesicular recycling. Our results suggest that LRRK2 modulates synaptic vesicle trafficking and distribution in neurons and in consequence participates in regulating the dynamics between vesicle pools inside the presynaptic bouton.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2011; 31(6):2225-37. DOI:10.1523/JNEUROSCI.3730-10.2011 · 6.34 Impact Factor
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