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 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.
Choi
Dong-Kug
DK
Department of Neurology, Columbia University, New York, New York 10032, USA.
Pennathur
Subramaniam
S
Perier
Celine
C
Tieu
Kim
K
Teismann
Peter
P
Wu
Du-Chu
DC
Jackson-Lewis
Vernice
V
Vila
Miquel
M
Vonsattel
Jean-Paul
JP
Heinecke
Jay W
JW
Przedborski
Serge
S
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
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