Myeloperoxidase Inhibition Ameliorates Multiple System Atrophy-Like Degeneration in a Transgenic Mouse Model
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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MPO expression level in reactive microglia was upregulated in the brains of MSA patients and a mouse model of MSA.
“MPO expression level in reactive microglia was upregulated in the brains of MSA patients and a mouse model of MSA.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [495]
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Self-citation
- Authors
- Stefanova, N., Georgievska, B., Eriksson, H., Poewe, W., & Wenning, G. K.
- Affiliations
- Innsbruck Medical University (AT)
- AstraZeneca (Sweden) (SE)
- Corresponding author
- Stefanova, Nadia
- Venue
- Neurotoxicity Research
- Published
- 2011-12-08
- Volume
- 21
- Issue
- 4
- Pages
- 393-404
- ISSN
- 1029-8428 (ISSN-L)
- 1476-3524
- OpenAlex
- W2024698496
- Cited by
- 111
- References
- 44
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 8 · 2023: 7 · 2022: 10 · 2021: 5 · 2020: 13 · 2019: 5 · 2018: 7 · 2017: 8 · 2016: 11 · 2015: 8 · 2014: 7 · 2013: 9 · 2012: 1
- FWCI
- 3.85
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neurotoxicity Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- multiple system atrophy, myeloperoxidase inhibition, synucleinopathies, 3-nitropropionic acid, oxidative stress, microglial activation, astrocyte activation, striatonigral degeneration, olivopontocerebellar atrophy, alpha-synuclein aggregates, neuroprotection, anti-inflammatory therapy, transgenic mouse model
- MeSH terms
- Aged, Animals, Brain, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Gliosis, Humans, Male, Mice, Transgenic, Middle Aged, Motor Activity, Peroxidase, Nerve Degeneration, Pyrimidinones, Pyrroles, Microglia, Multiple System Atrophy, Mice, alpha-Synuclein
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