Role Of Tyrosine Hydroxylase And Its Active Fragment On Parkinson's Disease

Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elder people; it is characterized by resting tremor, rigidity, bradykinesia and postural instability. It is caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) pars compacta, the depletion of neurotransmitter dopamine (DA) in the stratum and SN and the decrease of tyrosine hydroxylase (Tyrosine 3-monooxygenase, EC 1.14.16.2, TH) activity. DA is one of the most important molecules in accommodating body movement; the depletion of DA is the direct reason for abnormal motor behavior in PD. TH catalyzes the hydroxylation of 1-tyrosine to 1-dihydroxyphenylalanine (1-dopa), the rate-limiting step in the biosynthesis of DA. Thus we suppose that supplementation of exogenous TH in the source should improve the function of the dopaminergic nerve system and promote the ability of movement in PD. Human TH was found to have four isoforms (hTH1-4), among them, the TH1 has the highest specific enzymatic activity. The TH protein is composed of two major domains. The N-terminal portion of the protein bears the regulatory domain, and the C-terminal half forms the catalytic core, and the specific activity of TH catalytic domain without the regulatory domain is higher than that of the wild type enzyme. TH1 and its catalystic domain (THc) are supplied to treat PD, the intention is unique, and it is the first time both at home and abroad.TH and THc are 55, 40 ku by the molecular weight respectively, and are severely limited by the blood-brain barrier and cell membrane. To deliver the therapeutic proteins, TH and THc were linked to protein transduction domain (PTD) of the human immunodeficiency virus (HIV-1) TAT protein. PTD-TH and PTD-THc proteins were obtained by genetic engineering expression, and they were solubilized successfully. The results in vitro showed that the PTD-TH and PTD-THc passed through the SH-sy5y cells and located in cytoplasm; iv PTD-TH and PTD-THc proteins permeated across the blood-brain barrier, increased the level of TH in rat brains. The behavioral...