Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende
Erweiterte Suche
Anmelden
nach oben
Translational Stroke Research
Erschienen in: Translational Stroke Research 2/2018

25.08.2017 | Original Article

Protein Modifications with Ubiquitin as Response to Cerebral Ischemia-Reperfusion Injury

verfasst von: Karin Hochrainer

Erschienen in: Translational Stroke Research | Ausgabe 2/2018

Einloggen, um Zugang zu erhalten

Abstract

Post-translational protein modifications present an elegant and energy efficient way to dynamically reprogram cellular protein properties and functions in response to homeostatic imbalance. One such protein modification is the tagging of proteins with the small modifier ubiquitin that can have an impact on protein stability, localization, interaction dynamics, and function. Ubiquitination is vital to any eukaryotic cell under physiological conditions, but even more important under stress including oxidative, genotoxic, and heat stress, where ubiquitination levels are drastically increased. Elevated levels of ubiquitin-protein conjugates are also observed in the brain after focal and global cerebral ischemia. Post-ischemic ubiquitination is immediately induced with reperfusion and transiently detected in neurons with survival potential located in the peri-infarct area. This review aims to critically discuss current knowledge and controversies on protein ubiquitination after cerebral ischemia, with special emphasis on potential mechanisms leading to elevated ubiquitination and on target identification. Further, possible functional implications of post-ischemic ubiquitination, including a relationship to SUMOylation, a neuroprotective modification, will be highlighted. The elevation in ubiquitinated proteins following cerebral ischemia is a greatly under-explored research area, the better understanding of which may contribute to the development of novel stroke therapies.
Literatur
1.
Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, et al. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell. 2011;44(2):325–40.PubMedPubMedCentralCrossRef
2.
Ciechanover A, Heller H, Elias S, Haas AL, Hershko A. ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation. Proc Natl Acad Sci U S A. 1980;77(3):1365–8.PubMedPubMedCentralCrossRef
3.
Hershko A, Eytan E, Ciechanover A, Haas AL. Immunochemical analysis of the turnover of ubiquitin-protein conjugates in intact cells. Relationship to the breakdown of abnormal proteins. J Biol Chem. 1982;257(23):13964–70.PubMed
4.
Muratani M, Tansey WP. How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol. 2003;4(3):192–201.PubMedCrossRef
5.
Reed SI. Ratchets and clocks: the cell cycle, ubiquitylation and protein turnover. Nat Rev Mol Cell Biol. 2003;4(11):855–64.PubMedCrossRef
6.
Wang J, Maldonado MA. The ubiquitin-proteasome system and its role in inflammatory and autoimmune diseases. Cell Mol Immunol. 2006;3(4):255–61.PubMed
7.
Mukhopadhyay D, Riezman H. Proteasome-independent functions of ubiquitin in endocytosis and signaling. Science. 2007;315(5809):201–5.PubMedCrossRef
8.
Chen ZJ, Sun LJ. Nonproteolytic functions of ubiquitin in cell signaling. Mol Cell. 2009;33(3):275–86.PubMedCrossRef
9.
Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms. Biochim Biophys Acta. 2004;1695(1–3):55–72.PubMedCrossRef
10.
Caenepeel S, Charydczak G, Sudarsanam S, Hunter T, Manning G. The mouse kinome: discovery and comparative genomics of all mouse protein kinases. Proc Natl Acad Sci U S A. 2004;101(32):11707–12.PubMedPubMedCentralCrossRef
11.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298(5600):1912–34.PubMedCrossRef
12.
Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, et al. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005;123(5):773–86.PubMedCrossRef
13.
Kirisako T, Kamei K, Murata S, Kato M, Fukumoto H, Kanie M, et al. A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J. 2006;25(20):4877–87.PubMedPubMedCentralCrossRef
14.
15.
Ben-Saadon R, Zaaroor D, Ziv T, Ciechanover A. The polycomb protein Ring1B generates self atypical mixed ubiquitin chains required for its in vitro histone H2A ligase activity. Mol Cell. 2006;24(5):701–11.PubMedCrossRef
16.
Crosas B, Hanna J, Kirkpatrick DS, Zhang DP, Tone Y, Hathaway NA, et al. Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell. 2006;127(7):1401–13.PubMedCrossRef
17.
Kim HT, Kim KP, Lledias F, Kisselev AF, Scaglione KM, Skowyra D, et al. Certain pairs of ubiquitin-conjugating enzymes (E2s) and ubiquitin-protein ligases (E3s) synthesize nondegradable forked ubiquitin chains containing all possible isopeptide linkages. J Biol Chem. 2007;282(24):17375–86.PubMedCrossRef
18.
Peng J, Schwartz D, Elias JE, Thoreen CC, Cheng D, Marsischky G, et al. A proteomics approach to understanding protein ubiquitination. Nat Biotechnol. 2003;21(8):921–6.PubMedCrossRef
19.
20.
Johnson ES, Ma PC, Ota IM, Varshavsky A. A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem. 1995;270(29):17442–56.PubMedCrossRef
21.
Xu P, Duong DM, Seyfried NT, Cheng D, Xie Y, Robert J, et al. Quantitative proteomics reveals the function of unconventional ubiquitin chains in proteasomal degradation. Cell. 2009;137(1):133–45.PubMedPubMedCentralCrossRef
22.
Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009;37(Pt 5):937–53.PubMedCrossRef
23.
Komander D, Reyes-Turcu F, Licchesi JD, Odenwaelder P, Wilkinson KD, Barford D. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep. 2009;10(5):466–73.PubMedPubMedCentralCrossRef
24.
Tenno T, Fujiwara K, Tochio H, Iwai K, Morita EH, Hayashi H, et al. Structural basis for distinct roles of Lys63- and Lys48-linked polyubiquitin chains. Genes Cells. 2004;9(10):865–75.PubMedCrossRef
25.
Varadan R, Assfalg M, Haririnia A, Raasi S, Pickart C, Fushman D. Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin signaling. J Biol Chem. 2004;279(8):7055–63.PubMedCrossRef
26.
Varadan R, Walker O, Pickart C, Fushman D. Structural properties of polyubiquitin chains in solution. J Mol Biol. 2002;324(4):637–47.PubMedCrossRef
27.
Groll M, Ditzel L, Lowe J, Stock D, Bochtler M, Bartunik HD, et al. Structure of 20S proteasome from yeast at 2.4 a resolution. Nature. 1997;386(6624):463–71.PubMedCrossRef
28.
Unno M, Mizushima T, Morimoto Y, Tomisugi Y, Tanaka K, Yasuoka N, et al. The structure of the mammalian 20S proteasome at 2.75 a resolution. Structure. 2002;10(5):609–18.PubMedCrossRef
29.
Liu CW, Corboy MJ, DeMartino GN, Thomas PJ. Endoproteolytic activity of the proteasome. Science. 2003;299(5605):408–11.PubMedCrossRef
30.
31.
Glickman MH, Rubin DM, Coux O, Wefes I, Pfeifer G, Cjeka Z, et al. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell. 1998;94(5):615–23.PubMedCrossRef
32.
Verma R, Oania R, Graumann J, Deshaies RJ. Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system. Cell. 2004;118(1):99–110.PubMedCrossRef
33.
Verma R, Aravind L, Oania R, McDonald WH, Yates JR 3rd, Koonin EV, et al. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science. 2002;298(5593):611–5.PubMedCrossRef
34.
Yao T, Cohen RE. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature. 2002;419(6905):403–7.PubMedCrossRef
35.
Braun BC, Glickman M, Kraft R, Dahlmann B, Kloetzel PM, Finley D, et al. The base of the proteasome regulatory particle exhibits chaperone-like activity. Nat Cell Biol. 1999;1(4):221–6.PubMedCrossRef
36.
Dubiel W, Pratt G, Ferrell K, Rechsteiner M. Purification of an 11 S regulator of the multicatalytic protease. J Biol Chem. 1992;267(31):22369–77.PubMed
37.
38.
Aki M, Shimbara N, Takashina M, Akiyama K, Kagawa S, Tamura T, et al. Interferon-gamma induces different subunit organizations and functional diversity of proteasomes. J Biochem. 1994;115(2):257–69.PubMedCrossRef
39.
Pickering AM, Koop AL, Teoh CY, Ermak G, Grune T, Davies KJ. The immunoproteasome, the 20S proteasome and the PA28alphabeta proteasome regulator are oxidative-stress-adaptive proteolytic complexes. Biochem J. 2010;432(3):585–94.PubMedPubMedCentralCrossRef
40.
Kloetzel PM. Antigen processing by the proteasome. Nat Rev Mol Cell Biol. 2001;2(3):179–87.PubMedCrossRef
41.
Diaz-Hernandez M, Hernandez F, Martin-Aparicio E, Gomez-Ramos P, Moran MA, Castano JG, et al. Neuronal induction of the immunoproteasome in Huntington's disease. J Neurosci. 2003;23(37):11653–61.PubMed
42.
Orre M, Kamphuis W, Dooves S, Kooijman L, Chan ET, Kirk CJ, et al. Reactive glia show increased immunoproteasome activity in Alzheimer's disease. Brain. 2013;136(Pt 5):1415–31.PubMedCrossRef
43.
Puttaparthi K, Elliott JL. Non-neuronal induction of immunoproteasome subunits in an ALS model: possible mediation by cytokines. Exp Neurol. 2005;196(2):441–51.PubMedCrossRef
44.
Bingol B, Wang CF, Arnott D, Cheng D, Peng J, Sheng M. Autophosphorylated CaMKIIalpha acts as a scaffold to recruit proteasomes to dendritic spines. Cell. 2010;140(4):567–78.PubMedCrossRef
45.
Djakovic SN, Schwarz LA, Barylko B, DeMartino GN, Patrick GN. Regulation of the proteasome by neuronal activity and calcium/calmodulin-dependent protein kinase II. J Biol Chem. 2009;284(39):26655–65.PubMedPubMedCentralCrossRef
46.
Jarome TJ, Kwapis JL, Ruenzel WL, Helmstetter FJ. CaMKII, but not protein kinase a, regulates Rpt6 phosphorylation and proteasome activity during the formation of long-term memories. Front Behav Neurosci. 2013;7:115.PubMedPubMedCentral
47.
Lin JT, Chang WC, Chen HM, Lai HL, Chen CY, Tao MH, et al. Regulation of feedback between protein kinase a and the proteasome system worsens Huntington's disease. Mol Cell Biol. 2013;33(5):1073–84.PubMedPubMedCentralCrossRef
48.
Zhang F, Hu Y, Huang P, Toleman CA, Paterson AJ, Kudlow JE. Proteasome function is regulated by cyclic AMP-dependent protein kinase through phosphorylation of Rpt6. J Biol Chem. 2007;282(31):22460–71.PubMedCrossRef
49.
Ishii T, Sakurai T, Usami H, Uchida K. Oxidative modification of proteasome: identification of an oxidation-sensitive subunit in 26 S proteasome. Biochemistry. 2005;44(42):13893–901.PubMedCrossRef
50.
Liu K, Paterson AJ, Zhang F, McAndrew J, Fukuchi K, Wyss JM, et al. Accumulation of protein O-GlcNAc modification inhibits proteasomes in the brain and coincides with neuronal apoptosis in brain areas with high O-GlcNAc metabolism. J Neurochem. 2004;89(4):1044–55.PubMedCrossRef
51.
Zhang F, Su K, Yang X, Bowe DB, Paterson AJ, Kudlow JE. O-GlcNAc modification is an endogenous inhibitor of the proteasome. Cell. 2003;115(6):715–25.PubMedCrossRef
52.
Ullrich O, Reinheckel T, Sitte N, Hass R, Grune T, Davies KJ. Poly-ADP ribose polymerase activates nuclear proteasome to degrade oxidatively damaged histones. Proc Natl Acad Sci U S A. 1999;96(11):6223–8.PubMedPubMedCentralCrossRef
53.
Wang D, Fang C, Zong NC, Liem DA, Cadeiras M, Scruggs SB, et al. Regulation of acetylation restores proteolytic function of diseased myocardium in mouse and human. Mol Cell Proteomics. 2013;12(12):3793–802.PubMedPubMedCentralCrossRef
54.
Besche HC, Sha Z, Kukushkin NV, Peth A, Hock EM, Kim W, et al. Autoubiquitination of the 26S proteasome on Rpn13 regulates breakdown of ubiquitin conjugates. EMBO J. 2014;33(10):1159–76.PubMedPubMedCentralCrossRef
55.
Isasa M, Katz EJ, Kim W, Yugo V, Gonzalez S, Kirkpatrick DS, et al. Monoubiquitination of RPN10 regulates substrate recruitment to the proteasome. Mol Cell. 2010;38(5):733–45.PubMedPubMedCentralCrossRef
56.
Bianchetta MJ, Lam TT, Jones SN, Morabito MA. Cyclin-dependent kinase 5 regulates PSD-95 ubiquitination in neurons. J Neurosci. 2011;31(33):12029–35.PubMedPubMedCentralCrossRef
57.
Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, et al. FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell. 2009;136(1):123–35.PubMedCrossRef
58.
Schwarz LA, Hall BJ, Patrick GN. Activity-dependent ubiquitination of GluA1 mediates a distinct AMPA receptor endocytosis and sorting pathway. J Neurosci. 2010;30(49):16718–29.PubMedPubMedCentralCrossRef
59.
Zemoura K, Trumpler C, Benke D. Lys-63-linked ubiquitination of gamma-aminobutyric acid (GABA), type B1, at multiple sites by the E3 ligase mind bomb-2 targets GABAB receptors to lysosomal degradation. J Biol Chem. 2016;291(41):21682–93.PubMedPubMedCentralCrossRef
60.
Deng L, Wang C, Spencer E, Yang L, Braun A, You J, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103(2):351–61.PubMedCrossRef
61.
Kanayama A, Seth RB, Sun L, Ea CK, Hong M, Shaito A, et al. TAB2 and TAB3 activate the NF-kappaB pathway through binding to polyubiquitin chains. Mol Cell. 2004;15(4):535–48.PubMedCrossRef
62.
Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature. 2001;412(6844):346–51.PubMedCrossRef
63.
Xia ZP, Sun L, Chen X, Pineda G, Jiang X, Adhikari A, et al. Direct activation of protein kinases by unanchored polyubiquitin chains. Nature. 2009;461(7260):114–9.PubMedPubMedCentralCrossRef
64.
Ehlers MD. Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. Nat Neurosci. 2003;6(3):231–42.PubMedCrossRef
65.
Hamilton AM, Oh WC, Vega-Ramirez H, Stein IS, Hell JW, Patrick GN, et al. Activity-dependent growth of new dendritic spines is regulated by the proteasome. Neuron. 2012;74(6):1023–30.PubMedPubMedCentralCrossRef
66.
Lopez-Salon M, Alonso M, Vianna MR, Viola H. Mello e Souza T, Izquierdo I et al. the ubiquitin-proteasome cascade is required for mammalian long-term memory formation. Eur J Neurosci. 2001;14(11):1820–6.PubMedCrossRef
67.
Colledge M, Snyder EM, Crozier RA, Soderling JA, Jin Y, Langeberg LK, et al. Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression. Neuron. 2003;40(3):595–607.PubMedPubMedCentralCrossRef
68.
Shin SM, Zhang N, Hansen J, Gerges NZ, Pak DT, Sheng M, et al. GKAP orchestrates activity-dependent postsynaptic protein remodeling and homeostatic scaling. Nat Neurosci. 2012;15(12):1655–66.PubMedPubMedCentralCrossRef
69.
70.
Jurd R, Thornton C, Wang J, Luong K, Phamluong K, Kharazia V, et al. Mind bomb-2 is an E3 ligase that ubiquitinates the N-methyl-D-aspartate receptor NR2B subunit in a phosphorylation-dependent manner. J Biol Chem. 2008;283(1):301–10.PubMedCrossRef
71.
Saliba RS, Michels G, Jacob TC, Pangalos MN, Moss SJ. Activity-dependent ubiquitination of GABA(a) receptors regulates their accumulation at synaptic sites. J Neurosci. 2007;27(48):13341–51.PubMedCrossRef
72.
Campbell DS, Holt CE. Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation. Neuron. 2001;32(6):1013–26.PubMedCrossRef
73.
Watts RJ, Hoopfer ED, Luo L. Axon pruning during drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system. Neuron. 2003;38(6):871–85.PubMedCrossRef
74.
75.
Fornace AJ Jr, Alamo I Jr, Hollander MC, Lamoreaux E. Ubiquitin mRNA is a major stress-induced transcript in mammalian cells. Nucleic Acids Res. 1989;17(3):1215–30.PubMedPubMedCentralCrossRef
76.
Kaneko M, Iwase I, Yamasaki Y, Takai T, Wu Y, Kanemoto S, et al. Genome-wide identification and gene expression profiling of ubiquitin ligases for endoplasmic reticulum protein degradation. Sci Rep. 2016;6:30955.PubMedPubMedCentralCrossRef
77.
Qian SB, McDonough H, Boellmann F, Cyr DM, Patterson C. CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature. 2006;440(7083):551–5.PubMedPubMedCentralCrossRef
78.
Seufert W, Jentsch S. Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins. EMBO J. 1990;9(2):543–50.PubMedPubMedCentral
79.
Shang F, Gong X, Taylor A. Activity of ubiquitin-dependent pathway in response to oxidative stress. Ubiquitin-activating enzyme is transiently up-regulated. J Biol Chem. 1997;272(37):23086–93.PubMedCrossRef
80.
Amm I, Sommer T, Wolf DH. Protein quality control and elimination of protein waste: the role of the ubiquitin-proteasome system. Biochim Biophys Acta. 2014;1843(1):182–96.PubMedCrossRef
81.
Goldberg AL. Protein degradation and protection against misfolded or damaged proteins. Nature. 2003;426(6968):895–9.PubMedCrossRef
82.
Pickart CM. Ubiquitin and the stress response. In: Latchman DS, editor. Stress Proteins. Berlin, Heidelberg: Springer Berlin Heidelberg; 1999. p. 133–52.CrossRef
83.
Preston GM, Brodsky JL. The evolving role of ubiquitin modification in endoplasmic reticulum-associated degradation. Biochem J. 2017;474(4):445–69.PubMedPubMedCentralCrossRef
84.
Arnason T, Ellison MJ. Stress resistance in Saccharomyces Cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain. Mol Cell Biol. 1994;14(12):7876–83.PubMedPubMedCentralCrossRef
85.
Silva GM, Finley D, Vogel C. K63 polyubiquitination is a new modulator of the oxidative stress response. Nat Struct Mol Biol. 2015;22(2):116–23.PubMedPubMedCentralCrossRef
86.
Hayashi T, Takada K, Matsuda M. Changes in ubiquitin and ubiquitin-protein conjugates in the CA1 neurons after transient sublethal ischemia. Mol Chem Neuropathol. 1991;15(1):75–82.PubMedCrossRef
87.
Hayashi T, Takada K, Matsuda M. Post-transient ischemia increase in ubiquitin conjugates in the early reperfusion. Neuroreport. 1992;3(6):519–20.PubMedCrossRef
88.
Hu BR, Janelidze S, Ginsberg MD, Busto R, Perez-Pinzon M, Sick TJ, et al. Protein aggregation after focal brain ischemia and reperfusion. J Cereb Blood Flow Metab. 2001;21(7):865–75.PubMedCrossRef
89.
Hochrainer K, Jackman K, Anrather J, Iadecola C. Reperfusion rather than ischemia drives the formation of ubiquitin aggregates after middle cerebral artery occlusion. Stroke. 2012;43(8):2229–35.PubMedPubMedCentralCrossRef
90.
Gubellini P, Bisso GM, Ciofi-Luzzatto A, Fortuna S, Lorenzini P, Michalek H, et al. Ubiquitin-mediated stress response in a rat model of brain transient ischemia/hypoxia. Neurochem Res. 1997;22(1):93–100.PubMedCrossRef
91.
Vannucci SJ, Mummery R, Hawkes RB, Rider CC, Beesley PW. Hypoxia-ischemia induces a rapid elevation of ubiquitin conjugate levels and ubiquitin immunoreactivity in the immature rat brain. J Cereb Blood Flow Metab. 1998;18(4):376–85.PubMedCrossRef
92.
Hu BR, Martone ME, Jones YZ, Liu CL. Protein aggregation after transient cerebral ischemia. J Neurosci. 2000;20(9):3191–9.PubMed
93.
Liu CL, Martone ME, Hu BR. Protein ubiquitination in postsynaptic densities after transient cerebral ischemia. J Cereb Blood Flow Metab. 2004;24(11):1219–25.PubMedPubMedCentralCrossRef
94.
Liu JJ, Zhao H, Sung JH, Sun GH, Steinberg GK. Hypothermia blocks ischemic changes in ubiquitin distribution and levels following stroke. Neuroreport. 2006;17(16):1691–5.PubMedCrossRef
95.
Liu C, Chen S, Kamme F, Hu BR. Ischemic preconditioning prevents protein aggregation after transient cerebral ischemia. Neuroscience. 2005;134(1):69–80.PubMedPubMedCentralCrossRef
96.
Morimoto T, Ide T, Ihara Y, Tamura A, Kirino T. Transient ischemia depletes free ubiquitin in the gerbil hippocampal CA1 neurons. Am J Pathol. 1996;148(1):249–57.PubMedPubMedCentral
97.
Hayashi T, Takada K, Matsuda M. Subcellular distribution of ubiquitin-protein conjugates in the hippocampus following transient ischemia. J Neurosci Res. 1992;31(3):561–4.PubMedCrossRef
98.
Iwabuchi M, Sheng H, Thompson JW, Wang L, Dubois LG, Gooden D, et al. Characterization of the ubiquitin-modified proteome regulated by transient forebrain ischemia. J Cereb Blood Flow Metab. 2014;34(3):425–32.PubMedCrossRef
99.
Kamikubo T, Hayashi T, Ohkawa K. Lack of effect of transient ischemia on ubiquitin conjugation. Neurochem Res. 1995;20(4):391–4.PubMedCrossRef
100.
Hochrainer K, Jackman K, Benakis C, Anrather J, Iadecola C. SUMO2/3 is associated with ubiquitinated protein aggregates in the mouse neocortex after middle cerebral artery occlusion. J Cereb Blood Flow Metab. 2015;35(1):1–5.PubMedCrossRef
101.
Bedford L, Layfield R, Mayer RJ, Peng J, Xu P. Diverse polyubiquitin chains accumulate following 26S proteasomal dysfunction in mammalian neurones. Neurosci Lett. 2011;491(1):44–7.PubMedCrossRef
102.
Noga M, Hayashi T. Ubiquitin gene expression following transient forebrain ischemia. Brain Res Mol Brain Res. 1996;36(2):261–7.PubMedCrossRef
103.
Gautam V, Trinidad JC, Rimerman RA, Costa BM, Burlingame AL, Monaghan DT. Nedd4 is a specific E3 ubiquitin ligase for the NMDA receptor subunit GluN2D. Neuropharmacology. 2013;74:96–107.PubMedCrossRef
104.
Hung AY, Sung CC, Brito IL, Sheng M. Degradation of postsynaptic scaffold GKAP and regulation of dendritic spine morphology by the TRIM3 ubiquitin ligase in rat hippocampal neurons. PLoS One. 2010;5(3):e9842.PubMedPubMedCentralCrossRef
105.
Kato A, Rouach N, Nicoll RA, Bredt DS. Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination. Proc Natl Acad Sci U S A. 2005;102(15):5600–5.PubMedPubMedCentralCrossRef
106.
Cabral-Miranda F, Nicoloso-Simoes E, Adao-Novaes J, Chiodo V, Hauswirth WW, Linden R, et al. rAAV8-733-mediated gene transfer of CHIP/stub-1 prevents hippocampal neuronal death in experimental brain ischemia. Mol Ther. 2017;25(2):392–400.PubMedCrossRef
107.
Lackovic J, Howitt J, Callaway JK, Silke J, Bartlett P, Tan SS. Differential regulation of Nedd4 ubiquitin ligases and their adaptor protein Ndfip1 in a rat model of ischemic stroke. Exp Neurol. 2012;235(1):326–35.PubMedCrossRef
108.
Howitt J, Lackovic J, Low LH, Naguib A, Macintyre A, Goh CP, et al. Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. J Cell Biol. 2012;196(1):29–36.PubMedPubMedCentralCrossRef
109.
Mengesdorf T, Jensen PH, Mies G, Aufenberg C, Paschen W. Down-regulation of parkin protein in transient focal cerebral ischemia: a link between stroke and degenerative disease? Proc Natl Acad Sci U S A. 2002;99(23):15042–7.PubMedPubMedCentralCrossRef
110.
Tang J, Hu Z, Tan J, Yang S, Zeng L. Parkin protects against oxygen-glucose deprivation/reperfusion insult by promoting Drp1 degradation. Oxidative Med Cell Longev. 2016;2016:8474303.
111.
Doran JF, Jackson P, Kynoch PA, Thompson RJ. Isolation of PGP 9.5, a new human neurone-specific protein detected by high-resolution two-dimensional electrophoresis. J Neurochem. 1983;40(6):1542–7.PubMedCrossRef
112.
Kumar R, Jangir DK, Verma G, Shekhar S, Hanpude P, Kumar S, et al. S-nitrosylation of UCHL1 induces its structural instability and promotes alpha-synuclein aggregation. Sci Rep. 2017;7:44558.PubMedPubMedCentralCrossRef
113.
Zhang M, Cai F, Zhang S, Zhang S, Song W. Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer's progression in vivo. Sci Rep. 2014;4:7298.PubMedPubMedCentralCrossRef
114.
Liu H, Li W, Ahmad M, Miller TM, Rose ME, Poloyac SM, et al. Modification of ubiquitin-C-terminal hydrolase-L1 by cyclopentenone prostaglandins exacerbates hypoxic injury. Neurobiol Dis. 2011;41(2):318–28.PubMedCrossRef
115.
Shen H, Sikorska M, Leblanc J, Walker PR, Liu QY. Oxidative stress regulated expression of ubiquitin carboxyl-terminal hydrolase-L1: role in cell survival. Apoptosis. 2006;11(6):1049–59.PubMedCrossRef
116.
Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT Jr. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell. 2002;111(2):209–18.PubMedCrossRef
117.
Osaka H, Wang YL, Takada K, Takizawa S, Setsuie R, Li H, et al. Ubiquitin carboxy-terminal hydrolase L1 binds to and stabilizes monoubiquitin in neuron. Hum Mol Genet. 2003;12(16):1945–58.PubMedCrossRef
118.
Lee BH, Lee MJ, Park S, Oh DC, Elsasser S, Chen PC, et al. Enhancement of proteasome activity by a small-molecule inhibitor of USP14. Nature. 2010;467(7312):179–84.PubMedPubMedCentralCrossRef
119.
Lee JH, Shin SK, Jiang Y, Choi WH, Hong C, Kim DE, et al. Facilitated tau degradation by USP14 aptamers via enhanced proteasome activity. Sci Rep. 2015;5:10757.PubMedPubMedCentralCrossRef
120.
Min JW, Lu L, Freeling JL, Martin DS, Wang H. USP14 inhibitor attenuates cerebral ischemia/reperfusion-induced neuronal injury in mice. J Neurochem. 2017;140(5):826–33.PubMedPubMedCentralCrossRef
121.
Asai A, Tanahashi N, Qiu JH, Saito N, Chi S, Kawahara N, et al. Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia. J Cereb Blood Flow Metab. 2002;22(6):705–10.PubMedCrossRef
122.
Caldeira MV, Curcio M, Leal G, Salazar IL, Mele M, Santos AR, et al. Excitotoxic stimulation downregulates the ubiquitin-proteasome system through activation of NMDA receptors in cultured hippocampal neurons. Biochim Biophys Acta. 2013;1832(1):263–74.PubMedCrossRef
123.
124.
Kamikubo T, Hayashi T. Changes in proteasome activity following transient ischemia. Neurochem Int. 1996;28(2):209–12.PubMedCrossRef
125.
Keller JN, Huang FF, Zhu H, Yu J, Ho YS, Kindy TS. Oxidative stress-associated impairment of proteasome activity during ischemia-reperfusion injury. J Cereb Blood Flow Metab. 2000;20(10):1467–73.PubMedCrossRef
126.
Saito A, Hayashi T, Okuno S, Nishi T, Chan PH. Modulation of p53 degradation via MDM2-mediated ubiquitylation and the ubiquitin-proteasome system during reperfusion after stroke: role of oxidative stress. J Cereb Blood Flow Metab. 2005;25(2):267–80.PubMedCrossRef
127.
Tai HC, Besche H, Goldberg AL, Schuman EM. Characterization of the brain 26S proteasome and its interacting proteins. Front Mol Neurosci 2010;3:12.
128.
Kisselev AF, Goldberg AL. Monitoring activity and inhibition of 26S proteasomes with fluorogenic peptide substrates. Methods Enzymol. 2005;398:364–78.PubMedCrossRef
129.
130.
Huang Q, Wang H, Perry SW, Figueiredo-Pereira ME. Negative regulation of 26S proteasome stability via calpain-mediated cleavage of Rpn10 subunit upon mitochondrial dysfunction in neurons. J Biol Chem. 2013;288(17):12161–74.PubMedPubMedCentralCrossRef
131.
Bulteau AL, Lundberg KC, Humphries KM, Sadek HA, Szweda PA, Friguet B, et al. Oxidative modification and inactivation of the proteasome during coronary occlusion/reperfusion. J Biol Chem. 2001;276(32):30057–63.PubMedCrossRef
132.
Farout L, Mary J, Vinh J, Szweda LI, Friguet B. Inactivation of the proteasome by 4-hydroxy-2-nonenal is site specific and dependant on 20S proteasome subtypes. Arch Biochem Biophys. 2006;453(1):135–42.PubMedCrossRef
133.
134.
Liu Y, Lu L, Hettinger CL, Dong G, Zhang D, Rezvani K, et al. Ubiquilin-1 protects cells from oxidative stress and ischemic stroke caused tissue injury in mice. J Neurosci. 2014;34(8):2813–21.PubMedPubMedCentralCrossRef
135.
Dantuma NP, Lindsten K, Glas R, Jellne M, Masucci MG. Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells. Nat Biotechnol. 2000;18(5):538–43.PubMedCrossRef
136.
Buchan AM, Li H, Blackburn B. Neuroprotection achieved with a novel proteasome inhibitor which blocks NF-kappaB activation. Neuroreport. 2000;11(2):427–30.PubMedCrossRef
137.
Doeppner TR, Kaltwasser B, Kuckelkorn U, Henkelein P, Bretschneider E, Kilic E, et al. Systemic proteasome inhibition induces sustained post-stroke neurological recovery and neuroprotection via mechanisms involving reversal of peripheral immunosuppression and preservation of blood-brain-barrier integrity. Mol Neurobiol. 2016;53(9):6332–41.PubMedCrossRef
138.
Doeppner TR, Mlynarczuk-Bialy I, Kuckelkorn U, Kaltwasser B, Herz J, Hasan MR, et al. The novel proteasome inhibitor BSc2118 protects against cerebral ischaemia through HIF1A accumulation and enhanced angioneurogenesis. Brain. 2012;135(Pt 11):3282–97.PubMedCrossRef
139.
Phillips JB, Williams AJ, Adams J, Elliott PJ, Tortella FC. Proteasome inhibitor PS519 reduces infarction and attenuates leukocyte infiltration in a rat model of focal cerebral ischemia. Stroke. 2000;31(7):1686–93.PubMedCrossRef
140.
Williams AJ, Hale SL, Moffett JR, Dave JR, Elliott PJ, Adams J, et al. Delayed treatment with MLN519 reduces infarction and associated neurologic deficit caused by focal ischemic brain injury in rats via antiinflammatory mechanisms involving nuclear factor-kappaB activation, gliosis, and leukocyte infiltration. J Cereb Blood Flow Metab. 2003;23(1):75–87.PubMedCrossRef
141.
Zhang L, Zhang ZG, Buller B, Jiang J, Jiang Y, Zhao D, et al. Combination treatment with VELCADE and low-dose tissue plasminogen activator provides potent neuroprotection in aged rats after embolic focal ischemia. Stroke. 2010;41(5):1001–7.PubMedPubMedCentralCrossRef
142.
Qiu JH, Asai A, Chi S, Saito N, Hamada H, Kirino T. Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. J Neurosci. 2000;20(1):259–65.PubMed
143.
Meller R, Thompson SJ, Lusardi TA, Ordonez AN, Ashley MD, Jessick V, et al. Ubiquitin proteasome-mediated synaptic reorganization: a novel mechanism underlying rapid ischemic tolerance. J Neurosci. 2008;28(1):50–9.PubMedPubMedCentralCrossRef
144.
Zhang X, Yan H, Yuan Y, Gao J, Shen Z, Cheng Y, et al. Cerebral ischemia-reperfusion-induced autophagy protects against neuronal injury by mitochondrial clearance. Autophagy. 2013;9(9):1321–33.PubMedCrossRef
145.
146.
Yamashita K, Eguchi Y, Kajiwara K, Ito H. Mild hypothermia ameliorates ubiquitin synthesis and prevents delayed neuronal death in the gerbil hippocampus. Stroke. 1991;22(12):1574–81.PubMedCrossRef
147.
Ide T, Takada K, Qiu JH, Saito N, Kawahara N, Asai A, et al. Ubiquitin stress response in postischemic hippocampal neurons under nontolerant and tolerant conditions. J Cereb Blood Flow Metab. 1999;19(7):750–6.PubMedCrossRef
148.
Liang J, Yao J, Wang G, Wang Y, Wang B, Ge P. Ischemic Postconditioning protects neuronal death caused by cerebral ischemia and reperfusion via attenuating protein aggregation. Int J Med Sci. 2012;9(10):923–32.PubMedPubMedCentralCrossRef
149.
Ouyang YB, Xu L, Giffard RG. Geldanamycin treatment reduces delayed CA1 damage in mouse hippocampal organotypic cultures subjected to oxygen glucose deprivation. Neurosci Lett. 2005;380(3):229–33.PubMedCrossRef
150.
Hayashi T, Tanaka J, Kamikubo T, Takada K, Matsuda M. Increase in ubiquitin conjugates dependent on ischemic damage. Brain Res Mol Brain Res. 1993;620(1):171–3.
151.
Velickovska V, van Breukelen F. Ubiquitylation of proteins in livers of hibernating golden-mantled ground squirrels, Spermophilus Lateralis. Cryobiology. 2007;55(3):230–5.PubMedPubMedCentralCrossRef
152.
153.
154.
Ptak C, Wozniak RW. SUMO and nucleocytoplasmic transport. Adv Exp Med Biol. 2017;963:111–26.PubMedCrossRef
155.
Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, et al. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 2001;276(38):35368–74.PubMedCrossRef
156.
Sampson DA, Wang M, Matunis MJ. The small ubiquitin-like modifier-1 (SUMO-1) consensus sequence mediates Ubc9 binding and is essential for SUMO-1 modification. J Biol Chem. 2001;276(24):21664–9.PubMedCrossRef
157.
Xu J, He Y, Qiang B, Yuan J, Peng X, Pan XM. A novel method for high accuracy sumoylation site prediction from protein sequences. BMC Bioinformatics. 2008;9:8.PubMedPubMedCentralCrossRef
158.
Matunis MJ, Coutavas E, Blobel G. A novel ubiquitin-like modification modulates the partitioning of the ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J Cell Biol. 1996;135(6 Pt 1):1457–70.PubMedCrossRef
159.
Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET. Characterization of a second member of the sentrin family of ubiquitin-like proteins. J Biol Chem. 1998;273(18):11349–53.PubMedCrossRef
160.
Vertegaal AC, Andersen JS, Ogg SC, Hay RT, Mann M, Lamond AI. Distinct and overlapping sets of SUMO-1 and SUMO-2 target proteins revealed by quantitative proteomics. Mol Cell Proteomics. 2006;5(12):2298–310.PubMedCrossRef
161.
Nacerddine K, Lehembre F, Bhaumik M, Artus J, Cohen-Tannoudji M, Babinet C, et al. The SUMO pathway is essential for nuclear integrity and chromosome segregation in mice. Dev Cell. 2005;9(6):769–79.PubMedCrossRef
162.
Saitoh H, Hinchey J. Functional heterogeneity of small ubiquitin-related protein modifiers SUMO-1 versus SUMO-2/3. J Biol Chem. 2000;275(9):6252–8.PubMedCrossRef
163.
Golebiowski F, Matic I, Tatham MH, Cole C, Yin Y, Nakamura A, et al. System-wide changes to SUMO modifications in response to heat shock. Sci Signal. 2009;2(72):ra24.PubMedCrossRef
164.
Carbia-Nagashima A, Gerez J, Perez-Castro C, Paez-Pereda M, Silberstein S, Stalla GK, et al. RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia. Cell. 2007;131(2):309–23.PubMedCrossRef
165.
Kang X, Li J, Zou Y, Yi J, Zhang H, Cao M, et al. PIASy stimulates HIF1alpha SUMOylation and negatively regulates HIF1alpha activity in response to hypoxia. Oncogene. 2010;29(41):5568–78.PubMedCrossRef
166.
Shao R, Zhang FP, Tian F, Anders Friberg P, Wang X, Sjoland H, et al. Increase of SUMO-1 expression in response to hypoxia: direct interaction with HIF-1alpha in adult mouse brain and heart in vivo. FEBS Lett. 2004;569(1–3):293–300.PubMedCrossRef
167.
Sobko A, Ma H, Firtel RA. Regulated SUMOylation and ubiquitination of DdMEK1 is required for proper chemotaxis. Dev Cell. 2002;2(6):745–56.PubMedCrossRef
168.
Tatham MH, Geoffroy MC, Shen L, Plechanovova A, Hattersley N, Jaffray EG, et al. RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation. Nat Cell Biol. 2008;10(5):538–46.PubMedCrossRef
169.
Schimmel J, Larsen KM, Matic I, van Hagen M, Cox J, Mann M, et al. The ubiquitin-proteasome system is a key component of the SUMO-2/3 cycle. Mol Cell Proteomics. 2008;7(11):2107–22.PubMedCrossRef
170.
Uzunova K, Gottsche K, Miteva M, Weisshaar SR, Glanemann C, Schnellhardt M, et al. Ubiquitin-dependent proteolytic control of SUMO conjugates. J Biol Chem. 2007;282(47):34167–75.PubMedCrossRef
171.
Cheng J, Kang X, Zhang S, Yeh ET. SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell. 2007;131(3):584–95.PubMedPubMedCentralCrossRef
172.
Buschmann T, Fuchs SY, Lee CG, Pan ZQ, Ronai Z. SUMO-1 modification of Mdm2 prevents its self-ubiquitination and increases Mdm2 ability to ubiquitinate p53. Cell. 2000;101(7):753–62.PubMedCrossRef
173.
Meulmeester E, Kunze M, Hsiao HH, Urlaub H, Melchior F. Mechanism and consequences for paralog-specific sumoylation of ubiquitin-specific protease 25. Mol Cell. 2008;30(5):610–9.PubMedCrossRef
174.
Aillet F, Lopitz-Otsoa F, Egana I, Hjerpe R, Fraser P, Hay RT, et al. Heterologous SUMO-2/3-ubiquitin chains optimize IkappaBalpha degradation and NF-kappaB activity. PLoS One. 2012;7(12):e51672.PubMedPubMedCentralCrossRef
175.
Guzzo CM, Berndsen CE, Zhu J, Gupta V, Datta A, Greenberg RA, et al. RNF4-dependent hybrid SUMO-ubiquitin chains are signals for RAP80 and thereby mediate the recruitment of BRCA1 to sites of DNA damage. Sci Signal. 2012;5(253):ra88.PubMedPubMedCentralCrossRef
176.
Peters M, Wielsch B, Boltze J. The role of SUMOylation in cerebral hypoxia and ischemia. Neurochem Int. 2017;107:66–77.PubMedCrossRef
177.
Bernstock JD, Lee YJ, Peruzzotti-Jametti L, Southall N, Johnson KR, Maric D, et al. A novel quantitative high-throughput screen identifies drugs that both activate SUMO conjugation via the inhibition of microRNAs 182 and 183 and facilitate neuroprotection in a model of oxygen and glucose deprivation. J Cereb Blood Flow Metab. 2016;36(2):426–41.PubMedCrossRef
178.
Cimarosti H, Ashikaga E, Jaafari N, Dearden L, Rubin P, Wilkinson KA, et al. Enhanced SUMOylation and SENP-1 protein levels following oxygen and glucose deprivation in neurones. J Cereb Blood Flow Metab. 2012;32(1):17–22.PubMedCrossRef
179.
Datwyler AL, Lattig-Tunnemann G, Yang W, Paschen W, Lee SL, Dirnagl U, et al. SUMO2/3 conjugation is an endogenous neuroprotective mechanism. J Cereb Blood Flow Metab. 2011;31(11):2152–9.PubMedPubMedCentralCrossRef
180.
Lee YJ, Mou Y, Maric D, Klimanis D, Auh S, Hallenbeck JM. Elevated global SUMOylation in Ubc9 transgenic mice protects their brains against focal cerebral ischemic damage. PLoS One. 2011;6(10):e25852.PubMedPubMedCentralCrossRef
181.
Yang W, Sheng H, Warner DS, Paschen W. Transient focal cerebral ischemia induces a dramatic activation of small ubiquitin-like modifier conjugation. J Cereb Blood Flow Metab. 2008;28(5):892–6.PubMedCrossRef
182.
Yang W, Sheng H, Warner DS, Paschen W. Transient global cerebral ischemia induces a massive increase in protein sumoylation. J Cereb Blood Flow Metab. 2008;28(2):269–79.PubMedCrossRef
183.
Yang W, Sheng H, Thompson JW, Zhao S, Wang L, Miao P, et al. Small ubiquitin-like modifier 3-modified proteome regulated by brain ischemia in novel small ubiquitin-like modifier transgenic mice: putative protective proteins/pathways. Stroke. 2014;45(4):1115–22.PubMedPubMedCentralCrossRef
184.
Yang W, Thompson JW, Wang Z, Wang L, Sheng H, Foster MW, et al. Analysis of oxygen/glucose-deprivation-induced changes in SUMO3 conjugation using SILAC-based quantitative proteomics. J Proteome Res. 2012;11(2):1108–17.PubMedCrossRef
185.
Metadaten
Titel
Protein Modifications with Ubiquitin as Response to Cerebral Ischemia-Reperfusion Injury
verfasst von
Karin Hochrainer
Publikationsdatum
25.08.2017
Verlag
Springer US
Erschienen in
Translational Stroke Research / Ausgabe 2/2018
Print ISSN: 1868-4483
Elektronische ISSN: 1868-601X
DOI
https://doi.org/10.1007/s12975-017-0567-x

Weitere Artikel der Ausgabe 2/2018

Translational Stroke Research 2/2018 Zur Ausgabe

Original Article

Beneficial Effects of Delayed P7C3-A20 Treatment After Transient MCAO in Rats

Original Article

Proteinuria Predicts Resistance to Antiplatelet Therapy in Ischemic Stroke

Original Article

Ischemic Preconditioning Protects Astrocytes against Oxygen Glucose Deprivation Via the Nuclear Erythroid 2-Related Factor 2 Pathway

Original Article

Protective Effects of Autologous Bone Marrow Mononuclear Cells After Administering t-PA in an Embolic Stroke Model

Original Article

Delayed Recanalization Promotes Functional Recovery in Rats Following Permanent Middle Cerebral Artery Occlusion

Original Article

Increased Plasma Galectin-3 Preceding the Development of Delayed Cerebral Infarction and Eventual Poor Outcome in Non-Severe Aneurysmal Subarachnoid Hemorrhage

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Neurologie

23.04.2024 | Demenz | Nachrichten

Demenzkranke durch Antipsychotika vielfach gefährdet

23.04.2024 | Parkinson-Krankheit | Podcast | Nachrichten

Parkinson-Therapie im Wandel – aktuelle Leitlinie im Fokus
Professorin Dr. Claudia Trenkwalder, Neurologin

22.04.2024 | DGIM 2024 | Nachrichten

Auf diese Krankheiten bei Geflüchteten sollten Sie vorbereitet sein

19.04.2024 | AAN-Jahrestagung 2024 | Nachrichten

Hustenstiller lindert Agitation bei Alzheimer
weitere anzeigen

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise