Complexity of dopamine metabolism
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Complexity of dopamine metabolism Johannes Meiser† , Daniel Weindl† and Karsten Hiller* Abstract Parkinson’s disease (PD) coincides with a dramatic loss of dopaminergic neurons within the substantia nigra. A key player in the loss of dopaminergic neurons is oxidative stress. Dopamine (DA) metabolism itself is strongly linked to oxidative stress as its degradation generates reactive oxygen species (ROS) and DA oxidation can lead to endogenous neurotoxins whereas some DA derivatives show antioxidative effects. Therefore, DA metabolism is of special importance for neuronal redox-homeostasis and viability. In this review we highlight different aspects of dopamine metabolism in the context of PD and neurodegeneration. Since most reviews focus only on single aspects of the DA system, we will give a broader overview by looking at DA biosynthesis, sequestration, degradation and oxidation chemistry at the metabolic level, as well as at the transcriptional, translational and posttranslational regulation of all enzymes involved. This is followed by a short overview of cellular models currently used in PD research. Finally, we will address the topic from a medical point of view which directly aims to encounter PD. Keywords: Parkinson’s disease, Metabolism, Metabolomics, Dopamine, Oxidative stress, Tyrosine hydroxylase, Tetrahydrobiopterine, Aromatic L-amino acid decarboxylase, Catecholamines
Introduction The age-related Parkinson’s disease (PD) is the most common neurodegenerative motor disorder in the world, affecting millions of elderly people. The motor symptoms of PD, such as rigidity, tremor or bradykinesia, are caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta. Despite intensive research over the past years, there is no cure for this disease and even diagnosis of PD is complicated due to a lack of reliable diagnostic tests. There are sporadic and inheritable forms of PD. Sporadic PD is by far the most common, and thus represents the more pressing medical need. However, similarities in both forms have led to the assumption that there are common underlying molecular mechanisms [1,2]. Major causes of neurodegeneration are mitochondrial impairment and oxidative stress. In this context it is interesting to note that although the adult human brain constitutes only about 2% of body weight, it consumes about 20% of the body’s oxygen and glucose for the production of energy in the form of adenosine triphosphate *Correspondence: [email protected] † Equal contributor Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7, avenue des Hauts-Fourneaux, L-4362 Esch-Belval, Luxembourg
(ATP) [3]. Thus, this organ is particularly exposed to the consequences of mitochondrial energy metabolism malfunction and its resulting injurious transition. In addition to these well known parameters, the catecholamine (CA) metabolism is a unique feature of catecholaminergic neurons and represents an additional source for reactive oxygen species (ROS) production. Accord
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