Overview of tyrosine hydroxylase in Parkinson's disease.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in brain catecholamine biosynthesis, and tetrahydrobiopterin is its cofactor. Research has focused on identifying mechanisms of TH activity regulation. TH activity is modulated by the cofactor itself, and is enhanced by several kinases phosphorylating key serines in the TH regulatory domain. Aside from these, the mechanisms that control TH gene transcription and TH mRNA translation are also related with the regulation of TH activity. Parkinson's disease (PD) is characterized by severe loss of dopaminergic neurons and depletion of dopamine in substantia nigra. Reduction of TH expression results in diminished dopamine synthesis and leads to PD; thus TH is essential in the pathogenesy of PD. It has also been shown that dysregulation of TH activity will contribute to PD. For example, α-synuclein represses TH not only by inhibiting phosphorylation at Ser40 of TH, but also by stimulating protein phosphatase 2A activity, which decreases dopamine synthesis and leads to parkinsonism. Based on these studies of TH in PD pathogenesis, a therapeutic strategy aimed to improve striatal TH expression in PD has received wide interest. Evidence shows that using drugs or other treatment methods such as gene replacement therapy to increase nigrostriatal TH expression is an effective therapy for PD. Further investigation of TH regulatory mechanisms will not only provide additional drug targets for PD, but may also help to identify new PD therapeutics.