Complexity of dopamine metabolism

Cell Communication and Signaling Complexity of dopamine metabolism Johannes Meiser 0 Daniel Weindl 0 Karsten Hiller 0 Equal contributor Luxembourg Centre for Systems Biomedicine, University of Luxembourg , 7, avenue des Hauts-Fourneaux, L-4362 Esch-Belval , Luxembourg 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. Parkinson's disease; Metabolism; Metabolomics; Dopamine; Oxidative stress; Tyrosine hydroxylase; Tetrahydrobiopterine; Aromatic L-amino acid decarboxylase; Catecholamines - Introduction The age-related Parkinsons 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 bodys oxygen and glucose for the production of energy in the form of adenosine triphosphate (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. According to this prompted oxidative stress, brain tissue samples of post mortem PD patients comprise increased levels of lipid peroxidation in the substantia nigra [4]. Catecholamine metabolism might be especially crucial for cellular redox homeostasis and could be a trigger for ROS overload, i.e. ROS that can no longer be detoxified by the cell. To better understand the catecholamine metabolism and its consequences to cellular integrity, a systems approach on a metabolic level would be beneficial. Systems biology and personalized medicine have become a fast growing field and have been more and more advanced especially in the light of high computing power, low cost sequencing opportunities and complex networks, underlying disease pathologies. Cellular regulation typically operates on four levels, besides regulation of genome, transcriptome and proteome the metabolome is the fourth level of regulation. Altered metabolic levels have in turn impact on the level of genome, transcriptome and proteome. Analyzing the metabolome means to make a metabolic snapshot of the cell, which is challenging because metabolism has turnover rates in the range of seconds. Recent publications, that have been made possible by the advancement of new technologies, describe in detail the underlying molecular mechanisms favoring these metabolic changes. In terms of todays research these advancements pushed our limits and opened new horizons. Key technologies are very sensitive mass spectrometers coupled to gas or liquid chromatography and stable isotope labeling [5,6]. The simultaneous measurement of several hundred metabolites in one single sample is no longer a challenge [7]. However, the key advancement in all large scale and omics analyses is the valuable readout of these large data sets, from their respective software packages [8]. In terms of metabolomics, this means identifying significantly deregulated metabolites, calculating enzyme activities, tracing the metabolic fate of single metabolites and to even identify unknown metabolites. These advancements can be observed in the field of cancer research, which has evolved tremendously over the last years [9]. Different examples nicely demonstrate the adaptation of cellular metabolism as an result of genetic reorganization and the impact of metabolism on cellular and systemic functionality [10,11]. Mining the literature of the last decade and looking for data related to DA metabolism or CA metabolism in general also with respect to PD we felt that this area of research is underrated, at least in the field of metabolism. Most research has been based on genetic studies, since several genes could be successfully linked to a PD phenotype. But we should not forget that most cases of PD are still idiopathic, rather than of genetic heritage. Therefore, additional causes for the loss of dopaminergic (DAergic) neurons over time, should exist. One key player for DAergic cell death might be the DA metabolism itself, which serves as a major source of intracellular ROS production. In this review we present a detailed overview over DA metabolism in the central nervous system, integrating molecular and biochemical aspects. We will refer to informative articles that go deeper into the individual topics. On the origin of dopamine research DA was first prepared long before its importance as neurotransmitter was discovered. It was originally synthesized in 1910 because of the strong physiological effects, observed for other phenolic bases like epinephrine [12,13], but due to its comparatively low effect on arterial blood-pressure it was mostly overlooked. The first time DA was found to occur in an organism was as a pigmentbuilding metabolite in the plant Sarothamnus scoparius [14]. Later on, it was found to be a substrate of aromatic amino acid decarboxylase (AADC) [15]; which could be isolated from sympathetic ganglia [16] and other animal tissues [17]. DA is also prevalent in invertebra (...truncated)