Overview of Tyrosine Hydroxylase in Parkinson’s Disease

Abstract

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.

Neuroprotective effects of alkaloids fromPiper longumin a MPTP-induced mouse model of Parkinson’s disease

“…Moreover, TH is the rate-limiting enzyme in the synthesis of catecholamine neurotransmitters such as dopamine. TH activity is progressively decreased following the loss of dopamine neurons in the substantia nigra in PD patients (Zhu et al, 2012). Our results showed that PLA reduced the loss of TH-positive neurons in substantia nigra of MPTP mice in vivo.…”

Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands—A review

“…However, the reliability of the latter finding is debatable given a small sample of 10 patients was investigated and to the best of our knowledge these results have not been replicated or followed up on thus far. One reason TYR may not actually benefit every, if any, case of Parkinson's may be that the disorder is associated with reduced expression of the TH enzyme (Zhu et al, 2012), which converts TYR into L-DOPA. Low TH activity would contribute to decreased DA synthesis.…”

Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor

“…TH, the rate limiting enzyme in dopamine synthesis in the brain, is the gold standard marker in the identification of dopaminergic neurons. 33 Ventral diencephalic TH populations are highly sensitive to MPTP exposure, and a decreased TH population leads to a pronounced reduction in the number of dopaminergic cells in the diencephalon. 34 Of note, MPP + alone cannot effectively induce neurodegeneration with animal models as it cannot cross the blood−brain barrier.…”