37
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Unaltered Striatal Dopamine Release Levels in Young Parkin Knockout, Pink1 Knockout, DJ-1 Knockout and LRRK2 R1441G Transgenic Mice

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Parkinson's disease (PD) is one of the most prevalent neurodegenerative brain diseases; it is accompanied by extensive loss of dopamine (DA) neurons of the substantia nigra that project to the putamen, leading to impaired motor functions. Several genes have been associated with hereditary forms of the disease and transgenic mice have been developed by a number of groups to produce animal models of PD and to explore the basic functions of these genes. Surprisingly, most of the various mouse lines generated such as Parkin KO, Pink1 KO, DJ-1 KO and LRRK2 transgenic have been reported to lack degeneration of nigral DA neuron, one of the hallmarks of PD. However, modest impairments of motor behavior have been reported, suggesting the possibility that the models recapitulate at least some of the early stages of PD, including early dysfunction of DA axon terminals. To further evaluate this possibility, here we provide for the first time a systematic comparison of DA release in four different mouse lines, examined at a young age range, prior to potential age-dependent compensations. Using fast scan cyclic voltammetry in striatal sections prepared from young, 6–8 weeks old mice, we examined sub-second DA overflow evoked by single pulses and action potential trains. Unexpectedly, none of the models displayed any dysfunction of DA overflow or reuptake. These results, compatible with the lack of DA neuron loss in these models, suggest that molecular dysfunctions caused by the absence or mutation of these individual genes are not sufficient to perturb the function and survival of mouse DA neurons.

          Related collections

          Most cited references24

          • Record: found
          • Abstract: found
          • Article: not found

          Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.

          alpha-Synuclein (alpha-Syn) is a 14 kDa protein of unknown function that has been implicated in the pathophysiology of Parkinson's disease (PD). Here, we show that alpha-Syn-/- mice are viable and fertile, exhibit intact brain architecture, and possess a normal complement of dopaminergic cell bodies, fibers, and synapses. Nigrostriatal terminals of alpha-Syn-/- mice display a standard pattern of dopamine (DA) discharge and reuptake in response to simple electrical stimulation. However, they exhibit an increased release with paired stimuli that can be mimicked by elevated Ca2+. Concurrent with the altered DA release, alpha-Syn-/- mice display a reduction in striatal DA and an attenuation of DA-dependent locomotor response to amphetamine. These findings support the hypothesis that alpha-Syn is an essential presynaptic, activity-dependent negative regulator of DA neurotransmission.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death

            Summary Mutations in PINK1 cause autosomal recessive Parkinson's disease. PINK1 is a mitochondrial kinase of unknown function. We investigated calcium homeostasis and mitochondrial function in PINK1-deficient mammalian neurons. We demonstrate physiologically that PINK1 regulates calcium efflux from the mitochondria via the mitochondrial Na+/Ca2+ exchanger. PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload. We show that calcium overload stimulates reactive oxygen species (ROS) production via NADPH oxidase. ROS production inhibits the glucose transporter, reducing substrate delivery and causing impaired respiration. We demonstrate that impaired respiration may be restored by provision of mitochondrial complex I and II substrates. Taken together, reduced mitochondrial calcium capacity and increased ROS lower the threshold of opening of the mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells. Our findings propose a mechanism by which PINK1 dysfunction renders neurons vulnerable to cell death.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Mitochondrial dysfunction in Parkinson's disease: molecular mechanisms and pathophysiological consequences.

              Neurons are critically dependent on mitochondrial integrity based on specific morphological, biochemical, and physiological features. They are characterized by high rates of metabolic activity and need to respond promptly to activity-dependent fluctuations in bioenergetic demand. The dimensions and polarity of neurons require efficient transport of mitochondria to hot spots of energy consumption, such as presynaptic and postsynaptic sites. Moreover, the postmitotic state of neurons in combination with their exposure to intrinsic and extrinsic neuronal stress factors call for a high fidelity of mitochondrial quality control systems. Consequently, it is not surprising that mitochondrial alterations can promote neuronal dysfunction and degeneration. In particular, mitochondrial dysfunction has long been implicated in the etiopathogenesis of Parkinson's disease (PD), based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Substantial progress towards understanding the role of mitochondria in the disease process has been made by the identification and characterization of genes causing familial variants of PD. Studies on the function and dysfunction of these genes revealed that various aspects of mitochondrial biology appear to be affected in PD, comprising mitochondrial biogenesis, bioenergetics, dynamics, transport, and quality control.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                14 April 2014
                : 9
                : 4
                : e94826
                Affiliations
                [1 ]Departments of pharmacology and neurosciences, Central Nervous System Research Group, Faculty of Medicine, Université de Montréal, Montreal, Canada
                [2 ]School of Life Sciences and Technology, Harbin Institute of Technology, Harbin, China
                [3 ]Department of cellular and molecular medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada
                National Institutes of Health, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LT DSP. Performed the experiments: GS RKV. Analyzed the data: GS RKV. Contributed reagents/materials/analysis tools: HB PCM DSP. Wrote the paper: GS RKV PCM HB DSP LT.

                Article
                PONE-D-13-49513
                10.1371/journal.pone.0094826
                3986353
                24733019
                3b928c2c-778d-4052-9a61-9dbddea78c87
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 November 2013
                : 19 March 2014
                Page count
                Pages: 7
                Funding
                This work was funded by a Rapid Response award from the Michael J. Fox Foundation for Parkinson's Research to L.-E.T. as well as by a grant to L.-E.T. and D.S.P. from the Brain Canada Foundation and the Krembil Foundation. R.K.V. was supported by a Science without Borders fellowship from the Conselho Nacional de Pesquisa e Desenvolvimento (CNPq), Brazil. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Neurochemistry
                Neurochemicals
                Neurotransmitters
                Genetics
                Genetics of Disease
                Neuroscience
                Cellular Neuroscience
                Medicine and Health Sciences
                Neurology
                Neurodegenerative Diseases
                Movement Disorders
                Parkinson Disease
                Neurobiology of Disease and Regeneration
                Research and Analysis Methods
                Animal Models of Disease
                Model Organisms
                Animal Models
                Mouse Models
                Research Design
                Clinical Research Design

                Uncategorized
                Uncategorized

                Comments

                Comment on this article