74
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Increased Mitochondrial Calcium Sensitivity and Abnormal Expression of Innate Immunity Genes Precede Dopaminergic Defects in Pink1-Deficient 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

          Background

          PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca 2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1 −/− mice.

          Methods and Findings

          Purified brain mitochondria of Pink1 −/− mice showed impaired Ca 2+ storage capacity, resulting in increased Ca 2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1 −/− mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1 −/− mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1 −/− mice had increased levels of IL-1β, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1 −/− embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-β (NF-κB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1 −/− mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting.

          Conclusions

          Increased mitochondrial Ca 2+ sensitivity and JNK activity are early defects in Pink1 −/− mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1 −/− mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-κB activation may predispose neurons of Pink1 −/− mice to inflammation and injury-induced cell death.

          Related collections

          Most cited references118

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

          Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator.

          A stereological method for obtaining estimates of the total number of neurons in five major subdivisions of the rat hippocampus is described. The new method, the optical fractionator, combines two recent developments in stereology: a three-dimensional probe for counting neuronal nuclei, the optical disector, and a systematic uniform sampling scheme, the fractionator. The optical disector results in unbiased estimates of neuron number, i.e., estimates that are free of assumptions about neuron size and shape, are unaffected by lost caps and overprojection, and approach the true number of neurons in an unlimited manner as the number of samples is increased. The fractionator involves sampling a known fraction of a structural component. In the case of neuron number, a zero dimensional quantity, it provides estimates that are unaffected by shrinkage before, during, and after processing of the tissue. Because the fractionator involves systematic sampling, it also results in highly efficient estimates. Typically only 100-200 neurons must be counted in an animal to obtain a precision that is compatible with experimental studies. The methodology is compared with those used in earlier works involving estimates of neuron number in the rat hippocampus and a number of new stereological methods that have particular relevance to the quantitative study of the structure of the nervous system are briefly described in an appendix.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3.

            The cellular mechanisms that directly regulate the inflammatory response after Toll-like receptor (TLR) stimulation are unresolved at present. Here we report that glycogen synthase kinase 3 (GSK3) differentially regulates TLR-mediated production of pro- and anti-inflammatory cytokines. Stimulation of monocytes or peripheral blood mononuclear cells with TLR2, TLR4, TLR5 or TLR9 agonists induced substantial increases in interleukin 10 production while suppressing the release of proinflammatory cytokines after GSK3 inhibition. GSK3 regulated the inflammatory response by differentially affecting the nuclear amounts of transcription factors NF-kappaB subunit p65 and CREB interacting with the coactivator CBP. Administration of a GSK3 inhibitor potently suppressed the proinflammatory response in mice receiving lipopolysaccharide and mediated protection from endotoxin shock. These findings demonstrate a regulatory function for GSK3 in modulating the inflammatory response.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Regulation of innate immune responses in the brain.

              Microglial cells are the main innate immune cells of the complex cellular structure of the brain. These cells respond quickly to pathogens and injury, accumulate in regions of degeneration and produce a wide variety of pro-inflammatory molecules. These observations have resulted in active debate regarding the exact role of microglial cells in the brain and whether they have beneficial or detrimental functions. Careful targeting of these cells could have therapeutic benefits for several types of trauma and disease specific to the central nervous system. This Review discusses the molecular details underlying the innate immune response in the brain during infection, injury and disease.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                13 January 2011
                : 6
                : 1
                : e16038
                Affiliations
                [1 ]Department of Anatomy and Neurobiology, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America
                [2 ]Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America
                National Institutes of Health, United States of America
                Author notes

                Conceived and designed the experiments: HB PGS. Performed the experiments: ZH RSA JE JDP LZ WAC. Analyzed the data: HB PGS WAC. Wrote the paper: HB.

                Article
                PONE-D-10-00565
                10.1371/journal.pone.0016038
                3020954
                21249202
                a16995fe-496a-4541-8b57-6c0267ec9887
                Akundi et al. 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
                : 13 August 2010
                : 5 December 2010
                Page count
                Pages: 17
                Categories
                Research Article
                Biology
                Immunology
                Immunity
                Inflammation
                Innate Immunity
                Model Organisms
                Animal Models
                Mouse
                Molecular Cell Biology
                Signal Transduction
                Signaling Cascades
                c-Jun N-terminal kinase signaling cascade
                Cellular Stress Responses
                Gene Expression
                Neuroscience
                Molecular Neuroscience
                Signaling Pathways
                Neurochemistry
                Neurochemicals
                Dopamine
                Neurobiology of Disease and Regeneration
                Medicine
                Neurology
                Neurodegenerative Diseases
                Parkinson Disease

                Uncategorized
                Uncategorized

                Comments

                Comment on this article