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    ABSTRACT: Wingless/Int (Wnt) signalling pathways are signal transduction mechanisms that have been widely studied in the field of embryogenesis. Recent work has established a critical role for these pathways in brain development, especially of midbrain dopaminergic neurones. However, the fundamental importance of Wnt signalling for the normal function of mature neurones in the adult central nervous system has also lately been demonstrated by an increasing number of studies. Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide and is currently incurable. This debilitating disease is characterized by the progressive loss of a subset of midbrain dopaminergic neurones in the substantia nigra leading to typical extrapyramidal motor symptoms. The aetiology of PD is poorly understood but work performed over the last two decades has identified a growing number of genetic defects that underlie this condition. Here we review a growing body of data connecting genes implicated in PD-most notably the PARK genes-with Wnt signalling. These observations provide clues to the normal function of these proteins in healthy neurones and suggest that deregulated Wnt signalling might be a frequent pathomechanism leading to PD. These observations have implications for the pathogenesis and treatment of neurodegenerative diseases in general.
    Journal of Molecular Cell Biology 10/2013; 6(1). DOI:10.1093/jmcb/mjt037
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    ABSTRACT: The importance of leucine-rich repeat kinase 2 (LRRK2) to mature neurons is well-established, since mutations in PARK8, the gene encoding LRRK2, are the most common known cause of Parkinson's disease. Nonetheless, despite the LRRK2 knockout mouse having no overt neurodevelopmental defect, numerous lines of in vitro data point toward a central role for this protein in neurogenesis. Roles for LRRK2 have been described in many key processes, including neurite outgrowth and the regulation of microtubule dynamics. Moreover, LRRK2 has been implicated in cell cycle control, suggesting additional roles in neurogenesis that precede terminal differentiation. However, we contend that the suggested function of LRRK2 as a scaffolding protein at the heart of numerous Wnt signaling cascades provides the most tantalizing link to neurogenesis in the developing brain. Numerous lines of evidence show a critical requirement for multiple Wnt pathways in the development of certain brain regions, not least the dopaminergic neurons of the ventral mid-brain. In conclusion, these observations indicate a function of LRRK2 as a subtle yet critical mediator of the action of Wnt ligands on developing neurons. We suggest that LRRK2 loss- or gain-of-function are likely modifiers of developmental phenotypes seen in animal models of Wnt signaling deregulation, a hypothesis that can be tested by cross-breeding relevant genetically modified experimental strains.
    Frontiers in Cellular Neuroscience 05/2013; 7:82. DOI:10.3389/fncel.2013.00082
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    ABSTRACT: Kainate receptors (KARs) are members of the glutamate receptor family, which also includes two other ionotropic subtypes, i.e. NMDA- and AMPA-type receptors, and types I, II and III metabotropic glutamate receptors. KARs mediate synaptic transmission postynaptically through their ionotropic capacity, while presynaptically, they modulate the release of both GABA and glutamate through operationally diverse modus operandi. At hippocampal mossy fiber (MF)-CA3 synapses, KARs have a biphasic effect on glutamate release, such that, depending on the extent of their activation, a facilitation or depression of glutamate release can be observed. This modulation is posited to contribute to important roles of KARs in short- and long-term plasticity. Elucidation of the modes of action of KARs in their depression and facilitation of glutamate release is beginning to gather impetus. Here we will focus on the cellular mechanisms involved in the modulation of glutamate release by presynaptic KAR activation at MF-CA3 synapses, a field that has seen significant progress in recent years.
    Neurochemistry International 03/2013; DOI:10.1016/j.neuint.2013.03.012
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    ABSTRACT: Dendrites emerging from the cell bodies of neurons receive the majority of synaptic inputs. They possess a plethora of ion channels that are essential for the processing of these synaptic signals. To fully understand how dendritic ion channels influence neuronal information processing, various patch-clamp techniques that allow electrophysiological recordings to be made directly from dendrites have been developed. In this chapter, I describe one such method that is suitable for making electrophysiological recordings from the apical dendrites of hippocampal and cortical pyramidal neurons.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 998:303-9. DOI:10.1007/978-1-62703-351-0_24
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    ABSTRACT: Pharmacological and genetic evidence reveals that GABA(A) receptor (GABA(A)-R) expression and localization are modulated in response to acute and chronic ethanol (EtOH) exposure. To determine molecular mechanisms of GABA(A)-R plasticity in response to in vivo acute EtOH, we measured early time changes in GABA(A)-R subunit localization. Single doses of EtOH (3 g/kg via i.p. injection in rats) produced decreases in surface levels of GABA(A)-R α4 and δ subunits at 5-15 min post-EtOH in hippocampus CA1 and dentate gyrus, verifying our earlier report (Liang et al., 2007). Here we also examined the β3 subunit and its phosphorylation state during internalization. β3 also was internalized during 5-15 min after EtOH exposure, while phosphorylation of β3 was increased, then decreased at later times, ruling out β3 dephosphorylation-dependent endocytosis. As early as 5 min post-EtOH, there is an initial increase in association between the δ subunits with clathrin adaptor proteins AP2-μ2 revealed by coimmunoprecipitation, followed by a decrease in association 15 min post-EtOH. In vitro studies using glutathione S-transferase fused to the δ subunit intracellular domain (ICD) show that two regions, one containing a classical YxxΦ motif and the other an atypical R/K-rich motif, directly and differentially bind to AP2-μ2, with the former YRSV exhibiting higher affinity. Mutating both regions in the δ-ICD abolishes μ2 binding, providing a possible mechanism that can explain the rapid downregulation of extrasynaptic α4βδ-GABA(A)-R following in vivo EtOH administration, in which the δ-ICD increases in affinity for clathrin AP2-μ2 leading to endocytosis.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 12/2012; 32(49):17874-17881. DOI:10.1523/JNEUROSCI.2535-12.2012
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    ABSTRACT: PD (Parkinson's disease) is a devastating progressive motor disorder with no available cure. Over the last two decades, an increasing number of genetic defects have been found that cause familial and idiopathic forms of PD. In parallel, the importance of Wnt signalling pathways for the healthy functioning of the adult brain and the dysregulation of these pathways in neurodegenerative disease has become apparent. Cell biological functions disrupted in PD are partially controlled by Wnt signalling pathways and proteins encoded by PARK genes have been shown to modify Wnt signalling. This suggests the prospect of targeting Wnt signalling pathways to modify PD progression.
    Biochemical Society Transactions 10/2012; 40(5):1123-8. DOI:10.1042/BST20120122
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    ABSTRACT: 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.
    Human Molecular Genetics 08/2012; 21(22):4966-79. DOI:10.1093/hmg/dds342
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    ABSTRACT: Background and purpose: Parkinson's disease (PD) is characterized by progressive dopaminergic cell loss; however, the noradrenergic system exhibits degeneration as well. Noradrenergic deficit in PD may be responsible for certain non-motor symptoms of the pathology, including psychiatric disorders and cognitive decline. The aim of this study was to generate a pre-motor rodent model of PD with noradrenergic denervation, and to assess whether treatment with Exendin-4 (EX-4), a glucagon-like peptide 1 receptor agonist, could reverse impairment exhibited by our model. Experimental approach: We generated a model of PD utilizing N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) and 6-hydroxydopamine (6-OHDA) to create partial lesions of both the noradrenergic and dopaminergic systems, respectively. We then assessed the validity of our model using an array of behavioral paradigms and biochemical techniques. Finally, we administered EX-4 over a one week period to determine therapeutic efficacy. Key results: Our model exhibits anhedonia and decreased object recognition as indicated by a decrease in sucrose preference, increased immobility in the forced swim test, and reduced novel object exploration. Tissue and extracellular dopamine and noradrenaline were reduced in the frontal cortex and striatum. TH+ cell counts decreased in the locus coeruleus (LC) and substantia nigra (SN). Treatment with EX-4 reversed behavioral impairment and restored extracellular/ tissue levels of both dopamine and noradrenaline and TH+ cell counts. Conclusion and Implications: We conclude that early treatment with EX-4 may reverse certain neuropsychiatric dysfunction and restore dopamine and noradrenaline content. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
    British Journal of Pharmacology 07/2012; DOI:10.1111/j.1476-5381.2012.02100.x
  • BMJ (online) 03/2012; 344:e1628. DOI:10.1136/bmj.e1628
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    ABSTRACT: Central and peripheral 5-hydroxytryptamine (5-HT) receptors play a critical role in the regulation of micturition. Bolus doses of 5-HT(2A/2C) receptor agonists have been shown to activate the external urethral sphincter (EUS) and to inhibit micturition. This study was designed to determine the contribution of these two 5-HT receptor subtypes to activation of the EUS and inhibition of micturition utilising pharmacokinetic knowledge to better control drug exposure. Recordings of urethral and bladder pressure, EUS-Electromyogram (EMG), the micturition reflex induced by bladder filling, blood pressure and heart rate were made in anaesthetized female rats. The effects of intravenous (i.v.) infusions of the 5-HT(2) receptor agonist (2S)-1-(6-chloro-5-fluoroindol-1-yl)propan-2-amine fumarate (Ro 60-0175) in the absence or presence of the selective 5-HT(2C) receptor antagonist 6-chloro-5-methyl-N-[6-(2-methylpyridin-3-yl)oxypyridin-3-yl]-2,3-dihydroindole-1-carboxamide dihydrochloride (SB 242084) or 5-HT(2A) receptor antagonist (R)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]methanol (MDL-100,907) were studied on these variables. Continuous infusion of increasing concentrations of Ro 60-0175 only evoked EUS-EMG activity at the highest concentration, which was blocked by co-infusion of MDL-100,907 but not SB 242084. Urethral pressure was unaffected by any drug infusion. Ro 60-0175 at the lowest concentration inhibited the micturition reflex but as the concentration increased this was reversed to facilitation. SB 242084 blocked the inhibition while MDL-100,907 blocked the excitation. Activation of 5-HT(2A) not 5-HT(2C) receptors evoked EUS-EMG activity. In conclusion, 5-HT(2A) receptor activation facilitated the micturition reflex and evoked EUS-EMG while 5-HT(2C) receptor activation only inhibited the micturition reflex.
    European journal of pharmacology 02/2012; 682(1-3):142-52. DOI:10.1016/j.ejphar.2012.02.010
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