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Myeloperoxidase Inhibition Ameliorates Multiple System Atrophy-Like Degeneration in a Transgenic Mouse Model

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Abstract

Multiple system atrophy (MSA) is a rare and fatal α-synucleinopathy characterized by a distinctive oligodendrogliopathy with glial cytoplasmic inclusions and associated neuronal multisystem degeneration. The majority of patients presents with a rapidly progressive parkinsonian disorder and atypical features such as early autonomic failure and cerebellar ataxia. We have previously reported that complete MSA pathology can be modeled in transgenic mice overexpressing oligodendroglial α-synuclein under conditions of oxidative stress induced by 3-nitropropionic acid (3-NP) including striatonigral degeneration, olivopontocerebellar atrophy, astrogliosis, and microglial activation. Here, we show that myeloperoxidase (MPO), a key enzyme involved in the production of reactive oxygen species by phagocytic cells, is expressed in both human and mouse MSA brains. We also demonstrate that in the MSA mouse model, MPO inhibition reduces motor impairment and rescues vulnerable neurons in striatum, substantia nigra pars compacta, cerebellar cortex, pontine nuclei, and inferior olives. MPO inhibition is associated with suppression of microglial activation but does not affect 3-NP induced astrogliosis in the same regions. Finally, MPO inhibition results in reduced intracellular aggregates of α-synuclein. This study suggests that MPO inhibition may represent a novel candidate treatment strategy against MSA-like neurodegeneration acting through its anti-inflammatory and anti-oxidative properties.

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Acknowledgments

This study was supported by AstraZeneca, Sweden. Dr. Manuela Neumann from the Center for Neuropathology and Prion Research, Brain Bank, University of Munich, Germany provided the human material. The authors are grateful to Ms. Monika Hainzer for the excellent technical assistance. We would like to thank Ms. Anette Stålebring-Löwstedt, Dr. Lars Nilsson, and Dr. Hung Lam for support with evaluation of the plasma samples in relation to MPO-i exposure. The authors thank Dr. Markus Reindl for the helpful discussion and comments.

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Authors and Affiliations

  1. Division of Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Anichstr. 35, 6020, Innsbruck, Austria

    Nadia Stefanova, Werner Poewe & Gregor K. Wenning

  2. AstraZeneca AB, Research and Development Innovative Medicines, CNSP iMED Science Södertälje, 15185, Södertälje, Sweden

    Biljana Georgievska & Håkan Eriksson

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  1. Nadia Stefanova
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  2. Biljana Georgievska
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  5. Gregor K. Wenning
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Correspondence to Nadia Stefanova.

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Stefanova, N., Georgievska, B., Eriksson, H. et al. Myeloperoxidase Inhibition Ameliorates Multiple System Atrophy-Like Degeneration in a Transgenic Mouse Model. Neurotox Res 21, 393–404 (2012). https://doi.org/10.1007/s12640-011-9294-3

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  • DOI: https://doi.org/10.1007/s12640-011-9294-3

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