title: 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.
authors.affiliation: Division of Clinical Neurobiology, Department of Neurology, Innsbruck Medical University, Anichstr. 35, 6020 Innsbruck, Austria. nadia.stefanova@i-med.ac.at
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Biljana
authors.initials: B
authors.lastname: Georgievska
authors.forename: Håkan
authors.initials: H
authors.lastname: Eriksson
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005911:Gliosis / Q000188:drug therapy; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects; D019578:Multiple System Atrophy / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D009410:Nerve Degeneration / Q000188:drug therapy; D009195:Peroxidase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011744:Pyrimidinones / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C573698:1-(2-isopropoxyethyl)-2-thioxo-1,2,3,5-tetrahydro-pyrrolo(3,2-d)pyrimidin-4-one; D004791:Enzyme Inhibitors; D011744:Pyrimidinones; D011758:Pyrroles; D051844:alpha-Synuclein; D009195:Peroxidase