MOLECULAR ASPECTS OF THE DOPAMINERGIC NEUROTOXINS IN RELATION TO TYROSINE-HYDROXYLASE ISOFORMS

Since the discovery of N-methyl-4-phentl-1 2, 3, 6-tetrahydropyridine (MPTP) as a parkinsonism-producing, dopaminergic neurotoxin, efforts h ave been made to find MPTP-like neurotoxins in the brain of parkinsoni sm patients. Tyrosine hydroxylase (TH) is the key enzyme for dopamine biosynthesis, and has been known to be decreased in the activity and p rotein content in the nigrostriaral dopaminergic neurons of parkinsoni an patients and of the MPTP-induced parkinsonian animals. Humans and m onkeys are known to be highly susceptible to MPTP to produce parkinson ism. We have found that humans and monkeys have four isoforms (type -1 similar to-4) and two isoforms (type-1 and -2), respectively. Using t he quantitative reverse transcription-polymerase chain reaction (RT-PC R), all four types of TH mRNAs were found in the substantia nigra of t he control human brains examined. We found that parkinsonian brains ha d 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 com pared with control brains, while no significant differences were found between schizophrenic brains and normal ones. Since the decrease in A ADC 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 s ubstantia nigra. We also measured TH type-1 and type-2 mRNA contents i n the substantia nigra, locus coeruleus, and adrenal gland of normal m onkeys and in MPTP- produced parkinsonian monkeys (macaca fascicularis ) by the quantitative RT- PCR method. Marked decreaes 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 similar to-4 mRNA content in the substantia nigra of parkinsonian pat ients, and suggest that MPTP-treated monkeys closely replicate changes in TH isoforms in human Parkinson's disease.