Protective and toxic roles of dopamine in Parkinson's disease

Abstract

The molecular mechanisms causing the loss of dopaminergic neurons containing neuromelanin in the substantia nigra and responsible for motor symptoms of Parkinson's disease are still unknown. The discovery of genes associated with Parkinson's disease (such as alpha synuclein (SNCA), E3 ubiquitin protein ligase (parkin), DJ-1 (PARK7), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL-1), serine/ threonine-protein kinase (PINK-1), leucine-rich repeat kinase 2 (LRRK2), cation-transporting ATPase 13A1 (ATP13A), etc.) contributed enormously to basic research towards understanding the role of these proteins in the sporadic form of the disease. However, it is generally accepted by the scientific community that mitochondria dysfunction, alpha synuclein aggregation, dysfunction of protein degradation, oxidative stress and neuroinflammation are involved in neurodegeneration. Dopamine oxidation seems to be a complex pathway in which dopamine o-quinone, aminochrome and 5,6-indolequinone are formed. However, both dopamine o-quinone and 5,6-indolequinone are so unstable that is difficult to study and separate their roles in the degenerative process occurring in Parkinson's disease. Dopamine oxidation to dopamine o-quinone, aminochrome and 5,6-indolequinone seems to play an important role in the neurodegenerative processes of Parkinson's disease as aminochrome induces: (i) mitochondria dysfunction, (ii) formation and stabilization of neurotoxic protofibrils of alpha synuclein, (iii) protein degradation dysfunction of both proteasomal and lysosomal systems and (iv) oxidative stress. The neurotoxic effects of aminochrome in dopaminergic neurons can be inhibited by: (i) preventing dopamine oxidation of the transporter that takes up dopamine into monoaminergic vesicles with low pH and dopamine oxidative deamination catalyzed by monoamino oxidase (ii) dopamine o-quinone, aminochrome and 5,6-indolequinone polymerization to neuromelanin and (iii) two-electron reduction of aminochrome catalyzed by DT-diaphorase. Furthermore, dopamine conversion to NM seems to have a dual role, protective and toxic, depending mostly on the cellular context. Dopamine metabolismDopamine synthesis and storage Dopaminergic neurons are involved in motor activity, in which dopamine is synthesized, stored and released to intersynaptic space. Dopamine is synthesized from the amino acid tyrosine in two steps that occur in the cytosol: (i) hydroxylation of tyrosine to l-dihydroxyphenylanaline (l-dopa), a reaction catalyzed by tyrosine hydroxylase (TH) that requires oxygen and (ii) decarboxylation of l-dopa to dopamine, a reaction catalyzed by aromatic amino acid decarboxylase (AADC) that generates CO 2 . Interestingly, dopamine synthesis does not result in dopamine accumulation in the cytosol as a consequence that TH and AADC are associated with the vesicular monoaminergic transporter-2 (VMAT-2) generating a complex where tyrosine is converted to l-dopa that immediately decarboxylated to dopamine. The

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

“…DAQ and generates ROS, both of which have been indicated in the pathogenesis of PD (Linert et al, 1996;Segura-Aguilar et al, 2014;Sulzer and Zecca, 2000). Our previous studies (Wang et al, 2006(Wang et al, , 2011) support a critical role of quinoprotein adduct formation in the selective vulnerability of aged SN dopaminergic neurons.…”

“…3D and 4D). Given the facts that tyrosinase catalyzed DAQ formation is not accompanied by ROS generation (Segura-Aguilar et al, 2014;Solomon et al, 1996) and the total reaction time was reduced from 96 h to 20 min (comparing Figs. 3C and D, and 4C and D), these results suggest that the effects of Spots that showed strong Coomassie Blue stain but no or very weak NBT stain were indicated by squares.…”

“…When DA is present in the cytosol instead of its proper vesicular storage, it is prone to oxidation (Linert et al, 1996;Segura-Aguilar et al, 2014;Sulzer and Zecca, 2000), resulting in the generation of reactive dopamine oquinone (DAQ), reactive oxygen species (ROS) (Graham et al, 1978;Hastings, 1995;Sulzer and Zecca, 2000) and neurotoxicity (Caudle et al, 2007;Chen et al, 2008;Taylor et al, 2011). DAQ and its derivatives (aminochrome and 5,6-indolequinone) are electrophiles, which are readily susceptible to the attack by cellular nucleophiles, particularly the reduced sulfhydryls on reduced glutathione (GSH), free cysteine and cysteinyl proteins (Segura-Aguilar et al, 2014;Tse et al, 1976), leading to the formation of thiol-quinone adduct (Fornstedt et al, 1986;Graham et al, 1978;Hastings et al, 1996). Since cysteine residues are generally critical for biological activities, DAQ modification of cysteinyl proteins often leads to compromised protein function (Hastings, 2009).…”

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…Thus, 5-HT signaling is most typically associated with mood, anxiety, aggression, and appetite, with 5-HT signaling dysregulation linked to disorders such as depression, obsessive-compulsive disorder (OCD), anxiety disorders, and autism spectrum disorder (ASD) (for review, see Olivier, 2015). DA has received prominent attention for its role in circuits supporting reward, attention, and movement, with perturbed DA signaling associated with addiction, attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Parkinson's disease (Viggiano et al, 2004b;Segura-Aguilar et al, 2014;Howes et al, 2015;Nutt et al, 2015 ). NE plays a prominent role in arousal, attention, executive function, and stress responses (Harley, 2004;Viggiano et al, 2004a;Morilak et al, 2005), with disorders such as ADHD, posttraumatic stress disorder.…”

OMICS as Therapeutic Platform: Environmental Factors to Parkinson’s Disease

“…Conjugated Dopamine or combination pharmacological agents with cysteine can help stabilize the effects of PD by preventing the oxidation process of dopamine to dopamine o-quinone, aminochrome and 5,6-indolequinone. This treatment seems to be effective against disease progression [26,27]. Unfortunately long term treatment with levodopa (L-DOPA) will cause tardive dyskinesia in addition to having a malfunctioning nigrostriatal dopaminergic system [28,29].…”