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      Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

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          Abstract

          Background

          PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types.

          Methods

          Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts.

          Results

          In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age.

          In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients.

          Conclusions

          Thus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12974-017-0928-0) contains supplementary material, which is available to authorized users.

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          Most cited references147

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          PARKIN ubiquitin ligase mediates resistance to intracellular pathogens

          Summary Ubiquitin-mediated targeting of intracellular bacteria to the autophagy pathway is a key innate defense mechanism against invading microbes, including the important human pathogen Mycobacterium tuberculosis. However, the ubiquitin ligases responsible for catalyzing ubiquitin chains that surround intracellular bacteria are poorly understood. PARKIN is a ubiquitin ligase with a well-established role in mitophagy, and mutations in the PARKIN gene (Park2) lead to increased susceptibility to Parkinson’s disease. Surprisingly, genetic polymorphisms in the Park2 regulatory region are also associated with increased susceptibility to intracellular bacterial pathogens in humans, including Mycobacterium leprae and Salmonella typhi, but the function of PARKIN in immunity remains unexplored. Here we show that PARKIN plays a role in ubiquitin-mediated autophagy of M. tuberculosis. Both PARKIN-deficient mice and flies are sensitive to various intracellular bacterial infections, suggesting PARKIN plays a conserved role in metazoan innate defense. Moreover, our work reveals an unexpected functional link between mitophagy and infectious disease.
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            Parkinson's Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation.

            Antigen presentation is essential for establishing immune tolerance and for immune responses against infectious disease and cancer. Although antigen presentation can be mediated by autophagy, here we demonstrate a pathway for mitochondrial antigen presentation (MitAP) that relies on the generation and trafficking of mitochondrial-derived vesicles (MDVs) rather than on autophagy/mitophagy. We find that PINK1 and Parkin, two mitochondrial proteins linked to Parkinson's disease (PD), actively inhibit MDV formation and MitAP. In absence of PINK1 or Parkin, inflammatory conditions trigger MitAP in immune cells, both in vitro and in vivo. MitAP and the formation of MDVs require Rab9 and Sorting nexin 9, whose recruitment to mitochondria is inhibited by Parkin. The identification of PINK1 and Parkin as suppressors of an immune-response-eliciting pathway provoked by inflammation suggests new insights into PD pathology.
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              Mitochondria: diversity in the regulation of the NLRP3 inflammasome.

              Recent studies have identified new roles for mitochondria in the regulation of autoinflammatory processes. Emerging data suggests that the release of danger signals from mitochondria in response to stress and infection promotes the formation of the inflammatory signaling platform known as inflammasomes. Activation of inflammasomes by damaged mitochondria results in caspase-1-dependent secretion of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18, and an inflammatory form of cell death referred to as pyroptosis. Here, we review recently described mechanisms that have been proposed to be involved in mitochondria-mediated regulation of inflammasome activation and inflammation. In addition, we highlight how aberrant regulation of mitochondria-induced inflammasome activation centrally contributes to the inflammatory process that is responsible for obesity and associated metabolic diseases.
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                Author and article information

                Contributors
                sylviatorres494@gmail.com
                key@stud.uni-frankfurt.de
                Hans-Hermann.Hoepken@gmx.de
                glawar615@gmail.com
                lucievalek@googlemail.com
                roller.bastian@web.de
                michael_walter@email.de
                blasjmorales@hotmail.com
                Meierhof@molgen.mpg.de
                Patrick.Harter@kgu.de
                Michel.MITTELBRONN@lns.etat.lu
                tegeder@em.uni-frankfurt.de
                Gispert-Sanchez@em.uni-frankfurt.de
                auburger@em.uni-frankfurt.de
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                2 August 2017
                2 August 2017
                2017
                : 14
                : 154
                Affiliations
                [1 ]ISNI 0000 0004 1936 9721, GRID grid.7839.5, Experimental Neurology, , Goethe University Medical School, ; 60590 Frankfurt am Main, Germany
                [2 ]ISNI 0000 0004 1936 9721, GRID grid.7839.5, Institute of Clinical Pharmacology, , Goethe University Medical School, ; 60590 Frankfurt am Main, Germany
                [3 ]ISNI 0000 0004 1936 9721, GRID grid.7839.5, Edinger-Institute (Institute of Neurology), , Goethe University Medical School, ; 60590 Frankfurt am Main, Germany
                [4 ]ISNI 0000 0001 2190 1447, GRID grid.10392.39, Institute for Medical Genetics, , Eberhard-Karls-University of Tuebingen, ; 72076 Tuebingen, Germany
                [5 ]GRID grid.459499.c, Department of Neurology, , University Hospital San Cecilio, ; 18012 Granada, Spain
                [6 ]ISNI 0000 0000 9071 0620, GRID grid.419538.2, , Max Planck Institute for Molecular Genetics, ; Ihnestraße 63-73, 14195 Berlin, Germany
                [7 ]Luxembourg Centre of Neuropathology (LCNP), Luxembourg, Luxembourg
                [8 ]ISNI 0000 0004 0621 5272, GRID grid.419123.c, Department of Pathology, , Laboratoire National de Santé, ; Dudelange, Luxembourg
                [9 ]ISNI 0000 0001 2295 9843, GRID grid.16008.3f, Luxembourg Centre for Systems Biomedicine (LCSB), , University of Luxembourg, ; Esch-sur-Alzette, Luxembourg, Luxembourg
                [10 ]Department of Oncology, Luxembourg Institute of Health, NORLUX Neuro-Oncology Laboratory, Luxembourg, Luxembourg
                Article
                928
                10.1186/s12974-017-0928-0
                5541666
                28768533
                20c99ef4-e137-4029-9cc0-1de3424541ea
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 August 2016
                : 26 July 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: GI342/3-1
                Award ID: CRC1039 A03
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: 01GS08138
                Award ID: PTJ 0315584A
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: DLR 01EW1012
                Award Recipient :
                Funded by: Arthur Merx Stiftung Frankfurt
                Funded by: FundRef http://dx.doi.org/10.13039/501100001866, Fonds National de la Recherche Luxembourg;
                Award ID: FNR PEARL P16/BM/11192868
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Neurosciences
                parkinson’s disease,ubiquitin kinase pink1,mitochondrial dysfunction,antiviral response,neuroinflammation

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