Ablation of the Inflammatory Enzyme Myeloperoxidase Mitigates Features of Parkinson's Disease in Mice

Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we sh...

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Bibliographic Details
Published in:The Journal of neuroscience 2005-07, Vol.25 (28), p.6594-6600
Main Authors: Choi, Dong-Kug, Pennathur, Subramaniam, Perier, Celine, Tieu, Kim, Teismann, Peter, Wu, Du-Chu, Jackson-Lewis, Vernice, Vila, Miquel, Vonsattel, Jean-Paul, Heinecke, Jay W, Przedborski, Serge
Format: Article
Language:English
Subjects:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine - pharmacokinetics
Amyotrophic Lateral Sclerosis - enzymology
Animals
Brain - enzymology
Corpus Striatum - enzymology
Dopamine - analysis
Drug Evaluation, Preclinical
Enzyme Induction
Humans
Huntington Disease - enzymology
Hypochlorous Acid - analysis
Male
Mesencephalon - enzymology
Mice
Mice, Inbred C57BL
Mice, Knockout
Nerve Tissue Proteins - chemistry
Neurobiology of Disease
Neurons - drug effects
Neurons - enzymology
Oxidative Stress
Parkinson Disease - enzymology
Parkinsonian Disorders - enzymology
Peroxidase - biosynthesis
Peroxidase - deficiency
Peroxidase - genetics
Peroxidase - physiology
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - biosynthesis
Tyrosine - analogs & derivatives
Tyrosine - analysis
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Summary:Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0970-05.2005