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Abstract
Parkinson’s disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of Ldihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.
Keywords: Parkinson disease, tyrosine hydroxylase, dopamine, α-synuclein, neuroprotection, neurotrophic factors, L-DOPA.
CNS & Neurological Disorders - Drug Targets
Title:A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease
Volume: 11 Issue: 4
Author(s): Shams Tabrez, Nasimudeen R. Jabir, Shazi Shakil, Nigel H. Greig, Qamre Alam, Adel M. Abuzenadah, Ghazi A. Damanhouri and Mohammad A. Kamal
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Keywords: Parkinson disease, tyrosine hydroxylase, dopamine, α-synuclein, neuroprotection, neurotrophic factors, L-DOPA.
Abstract: Parkinson’s disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of Ldihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.
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Cite this article as:
Tabrez Shams, R. Jabir Nasimudeen, Shakil Shazi, H. Greig Nigel, Alam Qamre, M. Abuzenadah Adel, A. Damanhouri Ghazi and A. Kamal Mohammad, A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease, CNS & Neurological Disorders - Drug Targets 2012; 11 (4) . https://dx.doi.org/10.2174/187152712800792785
DOI https://dx.doi.org/10.2174/187152712800792785 |
Print ISSN 1871-5273 |
Publisher Name Bentham Science Publisher |
Online ISSN 1996-3181 |
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