Tyrosine hydroxylase and Parkinson's disease |
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Authors: | Jan Haavik Karen Toska |
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Institution: | (1) Department of Biochemistry and Molecular Biology, University of Bergen, N-5009 Bergen, Norway |
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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 ofl-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 hereditaryl-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 withl-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 thatl-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. |
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Keywords: | Neurodegeneration dopamine iron oxidant stress mutations pathogenesis etiology gene therapy transplantation |
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