Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons.
Parkinson's disease is characterized by a severe loss of dopaminergic neurons resulting in a range of motor deficits. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause a similar loss of dopaminergic neurons in the human midbrain with corresponding Parkinsonian symptoms. Several animal species have also shown sensitivity to MPTP, including primates, mice, goldfish, and, most recently, zebrafish. This study demonstrates that the effect of MPTP on dopaminergic neurons in zebrafish larvae is mediated by the same pathways that have been demonstrated in mammalian species. MPTP-induced neurodegeneration was prevented by co-incubation with either the monoamine oxidase-B (MAO-B) inhibitor l-deprenyl or the dopamine transporter (DAT) inhibitor nomifensine. Furthermore, targeted inactivation of the DAT gene by antisense morpholinos also protected neurons from MPTP damage. Thus, the mechanism for MPTP-induced dopaminergic neuron toxicity in mammals is conserved in zebrafish larvae. Effects on swimming behavior and touch response that result from MPTP damage are partially ameliorated by both l-deprenyl and DAT knockdown.
McKinley
Enid T
ET
Zygogen, 520 Kell Hall, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA.
Baranowski
Timothy C
TC
Blavo
Delali O
DO
Cato
Candace
C
Doan
Thanh N
TN
Rubinstein
Amy L
AL
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004298:Dopamine / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D018390:Gene Targeting; D020267:MPTP Poisoning / Q000473:pathology / Q000517:prevention & control*; D008995:Monoamine Oxidase; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009627:Nomifensine / Q000494:pharmacology / Q000627:therapeutic use*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology / Q000627:therapeutic use*; D012642:Selegiline / Q000494:pharmacology / Q000627:therapeutic use*; D013045:Species Specificity; D013550:Swimming; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis / Q000235:genetics; D015027:Zebrafish / Q000196:embryology / Q000254:growth & development
D050483:Dopamine Plasma Membrane Transport Proteins; D008996:Monoamine Oxidase Inhibitors; D009025:Morpholines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D020319:Oligodeoxyribonucleotides, Antisense; D009627:Nomifensine; D012642:Selegiline; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D004298:Dopamine