Tyrosine hydroxylase and Parkinson's disease

Abstract

A consistent neurochemical abnormality in Parkinson's disease (PD) is degeneration of dopaminergic neurons in substantia nigra, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of L-DOPA, the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Similarly, some patients with hereditary L-DOPA-responsive dystonia, a neurological disorder with clinical similarities to PD, have mutations in the TH gene and decreased TH activity and/or stability. Thus, a logical and efficient treatment strategy for PD is based on correcting or bypassing the enzyme deficiency by treatment with L-DOPA, DA agonists, inhibitors of DA metabolism, or brain grafts with cells expressing TH. A direct pathogenetic role of TH has also been suggested, as the enzyme is a source of reactive oxygen species (ROS) in vitro and a target for radical-mediated oxidative injury. Recently, it has been demonstrated that L-DOPA is effectively oxidized by mammalian TH in vitro, possibly contributing to the cytotoxic effects of DOPA. This enzyme may therefore be involved in the pathogenesis of PD at several different levels, in addition to being a promising candidate for developing new treatments of this disease.

Blood–Brain Barrier Transport of Therapeutics via Receptor-Mediation

“…The ubiquitous expression pattern of TfR has been advantageous in developing a BBB RMT-based therapeutic for Parkinson's disease (84,85). Deficiency in the striatum of tyrosine hydroxylase (TH), the catalyst in the rate-limiting step of the formation of dopamine, is a result of Parkinson's disease (86). Zhang et al (84,85) encapsulated a nonviral TH expression plasmid in a PEGylated liposome, and targeted it through the BBB using the OX26 antibody.…”

The Generation of Dopaminergic Neurons by Human Neural Stem Cells Is Enhanced by Bcl-XL, BothIn VitroandIn Vivo

“…HiB5 and HEK293T cells yielded a high percentage of TH ϩ clones. It is important to note at this point that hNS1 cells express both GTP-cyclohydrolase I (GTP-CH1, responsible for BH 4 synthesis) and aromatic amino acid decarboxylase (AADC; required for the conversion of L-DOPA to DA), thus allowing for TH being fully active and rendering the cells with a full catecholamine synthesis pathway (Haavik and Toska, 1998;Liste et al, 2004).…”

“…Practical, biological (cell survival and function), clinical, and in some countries, ethical and legal limitations have stimulated a research effort to find alternative sources to generate hDAergic neurons in a predictable manner and in sufficient numbers (Lindvall et al, 2004). hDAergic neurons undergo continuous oxidative stress imposed by their catecholaminergic neurotransmitter phenotype (Haavik and Toska, 1998;Olanow and Tatton, 1999;Stokes et al, 1999;Barzilai et al, 2001;Blum et al, 2001). TH activity, by itself, generates hydrogen peroxide, and this gets exacerbated further by the auto-oxidation of both L-3,4-dihydroxyphenylalanine (L-DOPA) and DA, contributing many other free radicals.…”

Anti-Parkinson’s Activity of Uncaria Rhynchophylla Extract on Rotenone Induced Parkinsonism Model in Male Albino Rats

“…This may be attributed to the negative effect of alpha-synuclein in PD [29]. This enzyme is a rate limiting step in the biosynthesis of catecholamines that catalyzes the conversion of tyrosine to L-DOPA, the precursor of dopamine, which is in turn converted into noradrenalin by dopamine-β-hydroxylase [30] The loss in TH activity and expression is thought to contribute to the L-DOPA deficiency observed in parkinson's disease [31]. The administration of URE into Parkinsonism induced rats produced an increase of DA and TH levels in groups (V and VI) compared to control group (-ve) at P < 0.05.…”