title: Ablation of the inflammatory enzyme myeloperoxidase mitigates features of Parkinson's disease in mice.
abstract: 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.
authors: Department of Neurology, Columbia University, New York, New York 10032, USA.
authors: Dong-Kug
authors: DK
authors: Choi
authors: Subramaniam
authors: S
authors: Pennathur
authors: Celine
authors: C
authors: Perier
authors: Kim
authors: K
authors: Tieu
authors: Peter
authors: P
authors: Teismann
authors: Du-Chu
authors: DC
authors: Wu
authors: Vernice
authors: V
authors: Jackson-Lewis
authors: Miquel
authors: M
authors: Vila
authors: Jean-Paul
authors: JP
authors: Vonsattel
authors: Jay W
authors: JW
authors: Heinecke
authors: Serge
authors: S
authors: Przedborski
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000493:pharmacokinetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology; D000818:Animals; D001921:Brain / Q000201:enzymology*; D003342:Corpus Striatum / Q000201:enzymology; D004298:Dopamine / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology; D006997:Hypochlorous Acid / Q000032:analysis; D008297:Male; D008636:Mesencephalon / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000737:chemistry; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000201:enzymology; D020734:Parkinsonian Disorders / Q000201:enzymology*; D009195:Peroxidase / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014443:Tyrosine; D006997:Hypochlorous Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D009195:Peroxidase; C087259:3-chlorotyrosine; D004298:Dopamine