Tyrosine hydroxylase in relation to Parkinson’s disease: a historical overview and future prospect

Abstract

Reduction in tyrosine hydroxylase (TH), the regulatory enzyme for dopamine (DA) biosynthesis, in the nigrostriatal DA region is a characteristic change in Parkinson’s disease. TH was discovered in 1964 as the first and regulatory enzyme in DA biosynthesis, and the specific decrease of TH activity in the nigrostriatal DA region of parkinsonian brains was established around 1975. It has been generally assumed that the decrease in TH activity in parkinsonian brain is due to a reduction in TH protein as a result of cell death of the nigrostriatal DA neurons by unidentified mechanisms. In fact, we found TH activity and TH protein to be decreased in parallel in parkinsonian brain. However, since the discovery of multiple forms of human TH in 1987, some molecular changes in TH protein in Parkinson’s disease are speculated. This speculation may be supported by the increase in homospecific activity (enzyme activity/enzyme protein) of residual TH in parkinsonian brain, in contrast to constant homospecific activity of TH in the striatum of parkinsonian mice treated with l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A molecular biology approach to TH in Parkinson’s disease is expected to reveal the molecular pathogenesis.