Nonmotor Symptoms of Parkinson's Disease Revealed in an Animal Model with Reduced Monoamine Storage Capacity

Center for Neurodegenerative Disease and Department of Environmental and Occupational Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 07/2009; 29(25):8103-13. DOI: 10.1523/JNEUROSCI.1495-09.2009
Source: PubMed


Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, culminating in severe motor symptoms, including resting tremor, rigidity, bradykinesia, and postural instability. In addition to motor deficits, there are a variety of nonmotor symptoms associated with PD. These symptoms generally precede the onset of motor symptoms, sometimes by years, and include anosmia, problems with gastrointestinal motility, sleep disturbances, sympathetic denervation, anxiety, and depression. Previously, we have shown that mice with a 95% genetic reduction in vesicular monoamine transporter expression (VMAT2-deficient, VMAT2 LO) display progressive loss of striatal dopamine, L-DOPA-responsive motor deficits, alpha-synuclein accumulation, and nigral dopaminergic cell loss. We hypothesized that since these animals exhibit deficits in other monoamine systems (norepinephrine and serotonin), which are known to regulate some of these behaviors, the VMAT2-deficient mice may display some of the nonmotor symptoms associated with PD. Here we report that the VMAT2-deficient mice demonstrate progressive deficits in olfactory discrimination, delayed gastric emptying, altered sleep latency, anxiety-like behavior, and age-dependent depressive behavior. These results suggest that the VMAT2-deficient mice may be a useful model of the nonmotor symptoms of PD. Furthermore, monoamine dysfunction may contribute to many of the nonmotor symptoms of PD, and interventions aimed at restoring monoamine function may be beneficial in treating the disease.

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    • "suggest that this comparison is relevant to the pathophysiology of PD since multiple subtypes of mammalian aminergic neurons are sensitive to the neurodegenerative processes that characterize this disease, including noradrenergic neurons of the locus coeruleus and serotonergic neurons in the raphe nuclei (Kuhn et al., 2011; Politis and Loane, 2011; Politis et al., 2012; Szot, 2012; Taylor et al., 2009). Using the fly NMJ, we observed striking differences in the effect of ziram on Type Ib glutamatergic versus Type II aminergic and suggest that these differences may be relevant to neurotoxic effects of ziram in mammals and perhaps PD patients. "
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    ABSTRACT: Multiple populations of aminergic neurons are affected in Parkinson's disease (PD), with serotonergic and noradrenergic loci responsible for some non-motor symptoms. Environmental toxins, such as the dithiocarbamate fungicide ziram, significantly increase the risk of developing PD and the attendant spectrum of both motor and non-motor symptoms. The mechanisms by which ziram and other environmental toxins increase the risk of PD, and the potential effects of these toxins on aminergic neurons, remain unclear. To determine the relative effects of ziram on the synaptic function of aminergic versus non-aminergic neurons, we used live-imaging at the Drosophila melanogaster larval neuromuscular junction (NMJ). In contrast to nearly all other studies of this model synapse, we imaged presynaptic function at both glutamatergic Type Ib and aminergic Type II boutons, the latter responsible for storage and release of octopamine, the invertebrate equivalent of noradrenalin. To quantify the kinetics of exo- and endo- cytosis, we employed an acid-sensitive form of GFP fused to the Drosophila vesicular monoamine transporter (DVMAT-pHluorin). Additional genetic probes were used to visualize intracellular calcium flux (GCaMP) and voltage changes (ArcLight). We find that at glutamatergic Type Ib terminals, exposure to ziram increases exocytosis and inhibits endocytosis. By contrast, at octopaminergic Type II terminals, ziram has no detectable effect on exocytosis and dramatically inhibits endocytosis. In contrast to other reports on the neuronal effects of ziram, these effects do not appear to result from perturbation of the UPS or calcium homeostasis. Unexpectedly, ziram also caused spontaneous and synchronized bursts of calcium influx (measured by GCaMP) and electrical activity (measured by ArcLight) at aminergic Type II, but not glutamatergic Type Ib, nerve terminals. These events are sensitive to both tetrodotoxin and cadmium chloride, and thus appear to represent spontaneous depolarizations followed by calcium influx into Type II terminals. We speculate that the differential effects of ziram on Type II versus Type Ib terminals may be relevant to the specific sensitivity of aminergic neurons in PD, and suggest that changes neuronal excitability could contribute to the increased risk for PD caused by exposure to ziram. We also suggest that the fly NMJ will be useful to explore the synaptic effects of other pesticides associated with an increased risk of PD.
    Experimental Neurology 10/2015; DOI:10.1016/j.expneurol.2015.09.017 · 4.70 Impact Factor
    • "Environmental toxin modeling À þ (25% increase of NREM sleep selectively during the active dark phase of light/ dark cycle) À À 39% increase during active phase -Slight reduction in the number of orexinergic neurons. -No other potential alterations were reported [85] VMAT 2 deficient mice Loss of vesicular monoamine transporter 2 NR NI À NI NI Alteration of monoamine neurotransmission [196] Gracile axonal dystrophy (gad) mice Deletion of Ubiquitin cterminal hydrolase NI NI þ NI NI Slight reduction in the number of orexinergic neurons [197] "
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    ABSTRACT: Parkinson disease is one of the neurodegenerative diseases that benefited the most from the use of non-human models. Consequently, significant advances have been made in the symptomatic treatments of the motor aspects of the disease. Unfortunately, this translational success has been tempered by the recognition of the debilitating aspect of multiple non-motor symptoms of the illness. Alterations of the sleep/wakefulness behavior experienced as insomnia, excessive daytime sleepiness, sleep/wake cycle fragmentation and REM sleep behavior disorder are among the non-motor symptoms that predate motor alterations and inevitably worsen over disease progression. The absence of adequate humanized animal models with the perfect phenocopy of these sleep alterations contribute undoubtedly to the lack of efficient therapies for these non-motor complications. In the context of developing efficient translational therapies, we provide an overview of the strengths and limitations of the various currently available models to replicate sleep alterations of Parkinson's disease. Our investigation reveals that although these models replicate dopaminergic deficiency and related parkinsonism, they rarely display a combination of sleep fragmentation and excessive daytime sleepiness and never REM sleep behavior disorder. In this light, we critically discuss the construct, face and predictive validities of both rodent and non-human primate animals to model the main sleep abnormalities experienced by patients with PD. We conclude by highlighting the need of integrating a network-based perspective in our modeling approach of such complex syndrome in order to celebrate valid translational models. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Sleep Medicine Reviews 02/2015; DOI:10.1016/j.smrv.2015.02.005 · 8.51 Impact Factor
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    • "The phenotype was robust, emerging by 3 months of age and persisting through 11 months. Taylor et al. (2009) reported significant hyposmia in a VMAT2-deficient mouse (VMAT2- Lo). These mice express only 5% of wild-type levels of VMAT2 and express features of Parkinson disease such as neuronal loss in the SNc, oxidative stress, and motor impairments. "
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    ABSTRACT: The motor impairments of Parkinson disease are its most salient feature, and thus these symptoms receive the most attention. However, many nonmotor symptoms are also prevalent and may range in severity from mild to incapacitating. Cognitive impairment, for example, affects more than half of Parkinson patients (Ebmeier et al., 1990; Williams-Gray et al., 2007). Psychiatric conditions such as anxiety, depression, impulsivity, and sleep disorders are also common among Parkinson patients. Indeed, Weintraub and Burn (2011) suggest that psychiatric complications are so common among Parkinson patients that the disease might be better conceptualized as a neurocognitive/psychiatric disorder. Although these symptoms are gaining more recognition clinically, modeling of nonmotor symptoms lags behind. Behaviorally, many well-validated tasks exist that can assess a range of complex psychiatric and neurological conditions that are comorbid with Parkinson disease. However, it is important to determine whether manipulations that model the motor symptoms of Parkinson disease also alter nonmotor behaviors, to investigate how treatments for the motor impairments affect the nonmotor symptoms, and to understand how the standard treatments for nonmotor symptoms interact with treatments for the motor symptoms. This chapter will review the methods and techniques used to assess the nonmotor symptoms in animals, along with the relevant biology in animal models of Parkinson disease. 23.2 ANXIETY Anxiety is considered first for several reasons. First, anxiety disorders are highly prevalent in Parkinson disease, affecting up to half of patients (reviewed in Gallagher and Schrag, 2012). Second, chronic anxiety
    Movement Disorders: Genetics and Models, 2nd edited by M. S. LeDoux, 10/2014: chapter 23: pages 387-412; Elsevier Academic Press., ISBN: 978-0-12-405195-9
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