Molecular aspects of the dopaminergic neurotoxins in relation to tyrosine hydroxylase isoforms

T. Nagatsu, H. Ichinose, T. Ohye

Research output: Contribution to journalArticle

Abstract

Since the discovery of N-methyl-4-phentl-1, 2, 3, 6-tetrahydropyridine (MPTP) as a parkinsonism-producing, dopaminergic neurotoxin, efforts have been made to find MPTP-like neurotoxins in the brain of parkinsonism patients. Tyrosine hydroxylase (TH) is the key enzyme for dopamine biosynthesis, and has been known to be decreased in the activity and protein content in the nigrosniaral dopaminergic neurons of parkinsonian patients and of the MPTP-induced parkinsonian animals. Humans and monkeys are known to be highly susceptible to MPTP to produce parkinsonism. We have found that humans and monkeys have four isoforms (type -1 ~-4) and two isoforms (type-1 and -2), respectively. Using the quantitative reverse transcription-polymerase chain reaction (RT-PCR), all four types of TH mRNAs were found in the substantia nigra of the control human brains examined. We found that parkinsonian brains had very low levels of the mRNAs of all four TH isoforms and the mRNA of aromatic L-amino acid decarboxylase (AADC) in the sbstantia nigra compared with control brains, while no significant differences were found between schizophrenic brains and normal ones. Since the decrease in AADC mRNA in parkinsonian brain was comparable to that in TH mRNA, the alteration of TH in Parkinson's disease would not be a primary event, but it would reflect the degeneration of dopaminergic neurons in the substantia nigra. We also measured TH type-1 and type-2 mRNA contents in the substantia nigra, locus coeruleus, and adrenal gland of normal monkeys and in MPTP- produced parkinsonian monkeys (macaca fascicularis) by the quantitative RT- PCR method. Marked decrease in TH mRNA type-1 and 2 content were observed specifically in the substantia nigra of the monkeys with MPTP-parkinsonism compared to control monkeys. These results are similar to the data showing marked decreases in TH type -1 ~-4 mRNA content in the substantia nigra of parkinsonian patients, and suggest that MPTP-treated monkeys closely replicate changes in TH isoforms in human Parkinson's disease.

Original languageEnglish
Pages (from-to)117-123
Number of pages7
JournalBiogenic Amines
Volume12
Issue number2
Publication statusPublished - 01-01-1996

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Neurotoxins
Tyrosine 3-Monooxygenase
Protein Isoforms
Haplorhini
Substantia Nigra
Parkinsonian Disorders
Messenger RNA
Brain
Dopaminergic Neurons
Parkinson Disease
Aromatic-L-Amino-Acid Decarboxylases
RNA Isoforms
Polymerase Chain Reaction
Carboxy-Lyases
Locus Coeruleus
Macaca fascicularis
Adrenal Glands
Reverse Transcription
Dopamine
Amino Acids

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Pharmacology

Cite this

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abstract = "Since the discovery of N-methyl-4-phentl-1, 2, 3, 6-tetrahydropyridine (MPTP) as a parkinsonism-producing, dopaminergic neurotoxin, efforts have been made to find MPTP-like neurotoxins in the brain of parkinsonism patients. Tyrosine hydroxylase (TH) is the key enzyme for dopamine biosynthesis, and has been known to be decreased in the activity and protein content in the nigrosniaral dopaminergic neurons of parkinsonian patients and of the MPTP-induced parkinsonian animals. Humans and monkeys are known to be highly susceptible to MPTP to produce parkinsonism. We have found that humans and monkeys have four isoforms (type -1 ~-4) and two isoforms (type-1 and -2), respectively. Using the quantitative reverse transcription-polymerase chain reaction (RT-PCR), all four types of TH mRNAs were found in the substantia nigra of the control human brains examined. We found that parkinsonian brains had very low levels of the mRNAs of all four TH isoforms and the mRNA of aromatic L-amino acid decarboxylase (AADC) in the sbstantia nigra compared with control brains, while no significant differences were found between schizophrenic brains and normal ones. Since the decrease in AADC mRNA in parkinsonian brain was comparable to that in TH mRNA, the alteration of TH in Parkinson's disease would not be a primary event, but it would reflect the degeneration of dopaminergic neurons in the substantia nigra. We also measured TH type-1 and type-2 mRNA contents in the substantia nigra, locus coeruleus, and adrenal gland of normal monkeys and in MPTP- produced parkinsonian monkeys (macaca fascicularis) by the quantitative RT- PCR method. Marked decrease in TH mRNA type-1 and 2 content were observed specifically in the substantia nigra of the monkeys with MPTP-parkinsonism compared to control monkeys. These results are similar to the data showing marked decreases in TH type -1 ~-4 mRNA content in the substantia nigra of parkinsonian patients, and suggest that MPTP-treated monkeys closely replicate changes in TH isoforms in human Parkinson's disease.",
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Molecular aspects of the dopaminergic neurotoxins in relation to tyrosine hydroxylase isoforms. / Nagatsu, T.; Ichinose, H.; Ohye, T.

In: Biogenic Amines, Vol. 12, No. 2, 01.01.1996, p. 117-123.

Research output: Contribution to journalArticle

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