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      Parkin and PINK1 mitigate STING-induced inflammation

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          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

          Although serum from Parkinson’s disease (PD) patients displays elevated levels of numerous pro-inflammatory cytokines including IL-6, TNFα, IL-1β, and IFNβ1, whether inflammation contributes to or is a consequence of neuronal loss remains unknown 1 . Mutations in Parkin, an E3 ubiquitin ligase, and PINK1, a ubiquitin kinase, cause early-onset PD 2, 3 . Working in the same biochemical pathway, PINK1 and Parkin remove damaged mitochondria from cells in culture and in animal models via a selective form of autophagy, called mitophagy 4 . The role of mitophagy in vivo, however, is unclear in part because mice lacking PINK1 or Parkin have no substantial PD-relevant phenotypes 57 . As mitochondrial stress can lead to the release of damage-associated molecular patterns (DAMPs) that can activate innate immunity 812 , mitophagy may mitigate inflammation. Here we report a strong inflammatory phenotype in both Parkin −/− and PINK1 −/− mice following exhaustive exercise (EE) and in Parkin −/−;Mutator mice, which accumulate mitochondrial DNA mutations with age 13, 14 . Inflammation resulting from both EE and mtDNA mutation is completely rescued by concurrent loss of STING, a central regulator of the type I Interferon response to cytosolic DNA 15, 16 . The loss of dopaminergic (DA) neurons from the substantia nigra pars compacta (SNc) and the motor defect observed in aged Parkin −/−;Mutator mice are also rescued by loss of STING, suggesting that inflammation facilitates this phenotype. Humans with mono- and biallelic Parkin mutations also display elevated cytokines. These results support a role for PINK1- and Parkin-mediated mitophagy in restraining innate immunity.

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          Most cited references 41

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          A role for mitochondria in NLRP3 inflammasome activation.

          An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
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            Skyline: an open source document editor for creating and analyzing targeted proteomics experiments.

            Skyline is a Windows client application for targeted proteomics method creation and quantitative data analysis. It is open source and freely available for academic and commercial use. The Skyline user interface simplifies the development of mass spectrometer methods and the analysis of data from targeted proteomics experiments performed using selected reaction monitoring (SRM). Skyline supports using and creating MS/MS spectral libraries from a wide variety of sources to choose SRM filters and verify results based on previously observed ion trap data. Skyline exports transition lists to and imports the native output files from Agilent, Applied Biosystems, Thermo Fisher Scientific and Waters triple quadrupole instruments, seamlessly connecting mass spectrometer output back to the experimental design document. The fast and compact Skyline file format is easily shared, even for experiments requiring many sample injections. A rich array of graphs displays results and provides powerful tools for inspecting data integrity as data are acquired, helping instrument operators to identify problems early. The Skyline dynamic report designer exports tabular data from the Skyline document model for in-depth analysis with common statistical tools. Single-click, self-updating web installation is available at http://proteome.gs.washington.edu/software/skyline. This web site also provides access to instructional videos, a support board, an issues list and a link to the source code project.
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              Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.

              Parkinson's disease is a common neurodegenerative disease with complex clinical features. Autosomal recessive juvenile parkinsonism (AR-JP) maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253; the former is deleted in one Japanese AR-JP patient. By positional cloning within this microdeletion, we have now isolated a complementary DNA done of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3-7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product 'Parkin'.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                17 August 2018
                22 August 2018
                September 2018
                15 July 2020
                : 561
                : 7722
                : 258-262
                Affiliations
                [1 ]Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
                [2 ]Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA
                [3 ]Transgenics Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, Maryland 20892, USA
                [4 ]Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
                [5 ]The Protein/Peptide Sequencing Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
                [6 ]Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
                [7 ]Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
                Author notes

                Author Contribution

                The project was conceived by D.A.S., J.M. and R.J.Y. Mouse experiments including EE, sample collection and behavioral studies were conducted by D.A.S. Serum analysis was performed by J.M. Mass spectrometry was performed by L.H. and Y.L. Neuron counting was performed by X.C. and H.C. mt-Keima analysis was performed by N.S. LRRK2 mutant mice were exercised by T.F. J.L.B and Z.Z. provided technical assistance. Human patient samples were provided by D.P.N., M.B. and C.K. Writing and editing by D.A.S., J.M., C.K. and R.J.Y. Funding was provided to J.M., H.C, D.P.N, C.K. and R.J.Y.

                Corresponding author: Richard J. Youle, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA, youler@ 123456ninds.nih.gov
                Article
                NIHMS1500754
                10.1038/s41586-018-0448-9
                7362342
                30135585

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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