Neurodegenerativer Prozess bei Morbus Parkinson: Rolle der Myeloperoxidase

Zusammenfassung

Die Myeloperoxidase (MPO) ist ein Hämoprotein, das an der unspezifischen Immunantwort beteiligt ist. Bei diesem Prozess wird Hypochlorsäure freigesetzt, die mit Lipiden und Proteinen reagiert und somit zur Zellschädigung führt. Wir konnten zeigen, dass sowohl MPO wie auch Biomarker die eine MPO Aktivierung zeigen (3-Chlorotyrosin), im 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridin (MPTP)-Modell des Morbus Parkinson und im post-mortem Gewebe von Parkinson Patienten erhöht sind. Die genetische Ausschaltung der MPO führt zu einem neuroprotektiven Effekt im MPTP-Modell des Morbus Parkinson. In diesem Übersichtsartikel beschreiben wir die verschiedenen Funktionen der MPO und wie diese zum Zelluntergang im Morbus Parkinson beitragen.

Abstract

Myeloperoxidase (MPO) is a hemoprotein which is involved in the unspecific immune response. In this process hypochloric acid is released. Hypochloric acid can react with lipids and proteins and thus lead to cell damage. We were able to show that MPO, as well as a biomarker for MPO – 3-Chlorotyrosine – are upregulated in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model of Parkinson’s disease as well as in the disease itself. Ablation of MPO resulted in a neuroprotective effect in the MPTP-model. Herein we describe the different function of MPO, and how these can lead to the cellular demise as seen in Parkinson’s disease.

Schlüsselwörter

Myeloperoxidase - Morbus Parkinson - MPTP - neutrophile Granulozyten - Astrozyten - Gliose - Neurodegeneration

Keywords

myeloperoxidase - Parkinson’s disease - MPTP - neutrophils - Aastrocytes - gliosis - neurodegeneration

• Literatur

• 1 Choi DK, Pennathur S, Perier C et al. Ablation of the inflammatory enzyme myeloperoxidase mitigates features of parkinson's disease in mice. J Neurosci 2005; 25: 6594-6600
• 2 Forno LS, DeLanney LE, Irwin I et al. Astrocytes and parkinson's disease. Prog Brain Res 1992; 94: 429-436
• 3 Gaut JP, Yeh GC, Tran HD et al. Neutrophils employ the myeloperoxidase system to generate antimicrobial brominating and chlorinating oxidants during sepsis. Proc Natl Acad Sci USA 2001; 98: 11961-11966
• 4 Huh SH, Chung YC, Piao Y et al. Ethyl pyruvate rescues nigrostriatal dopaminergic neurons by regulating glial activation in a mouse model of parkinson's disease. J Immunol 2011; 187: 960-969
• 5 Lau D, Mollnau H, Eiserich JP et al. Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins. Proc Natl Acad Sci U S A 2005; 102: 431-436
• 6 Liberatore G, Jackson-Lewis V, Vukosavic S et al. Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of parkinson's disease. Nat Med 1999; 5: 1403-1409
• 7 Malle E, Furtmuller PG, Sattler W et al. Myeloperoxidase: A target for new drug development?. Br J Pharmacol 2007; 152: 838-854
• 8 Pennathur S, Jackson-Lewis V, Przedborski S et al. Mass spectrometric quantification of 3-nitrotyrosine, ortho-tyrosine and O,O'-dityrosine in brain tissue of MPTP-treated mice, a model of oxidative stress in parkinson's disease. J Biol Chem 1999; 274: 34621-34628
• 9 van der Vliet A, Eiserich JP, Halliwell B et al. Formation of reactive nitrogen species during peroxidase-catalyzed oxidation of nitrite. A potential additional mechanism of nitric oxide-dependent toxicity. J Biol Chem 1997; 272: 7617-7625
• 10 Wu DC, Teismann P, Tieu K et al. NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of parkinson's disease. Proc Natl Acad Sci U S A 2003; 100: 6145-6150
• 11 Astra Zeneca. Investigating safety, tolerability and pk when giving single and fractionated doses of AZD3241 to healthy volunteers. http://www.astrazenecaclinicaltrials.com/diseases-and-conditions/diseaseandconditions/?itemId=8595333 Letzter Zugriff: 12.11.2013