A Potential Role for Cyclized Quinones Derived from Dopamine, DOPA, and 3,4-Dihydroxyphenylacetic Acid in Proteasomal Inhibition

Abstract

We examined the ability of oxidation products of dopamine, DOPA, and 3,4-dihydroxyphenylacetic acid (DOPAC) to inhibit proteasomal activity. Dopamine, DOPA, and DOPAC underwent tyrosinase-catalyzed oxidation to generate aminochrome, dopachrome, and furanoquinone, respectively. In these studies, the oxidation of dopamine by tyrosinase generated product(s) that inhibited the proteasome, and proteasomal inhibition correlated with the presence of the UV-visible spectrum of aminochrome. The addition of superoxide dismutase and catalase did not prevent proteasomal inhibition. The addition of NADH and the quinone reductase NAD(P)H:quinone oxidoreductase 1 (NQO1) protected against aminochromeinduced proteasome inhibition. Although NQO1 protected against dopamine-induced proteasomal inhibition, the metabolism of aminochrome by NQO1 led to oxygen uptake because of the generation of a redox-labile cyclized hydroquinone, further demonstrating the lack of involvement of oxygen radicals in proteasomal inhibition. DOPA underwent tyrosinase-catalyzed oxidation to form dopachrome, and similar to aminochrome, proteasomal inhibition correlated with the presence of a dopachrome UV-visible spectrum. The inclusion of NQO1 did not protect against proteasomal inhibition induced by dopachrome. Oxidation of DOPAC by tyrosinase generated furanoquinone, which was a poor proteasome inhibitor. These studies demonstrate that oxidation products, including cyclized quinones derived from dopamine and related compounds, rather than oxygen radicals have the ability to inhibit the proteasome. They also suggest an important protective role for NQO1 in protecting against dopamine-induced proteasomal inhibition. The ability of endogenous intermediates formed during dopaminergic metabolism to cause proteasomal inhibition provides a potential basis for the selectivity of dopaminergic neuron damage in Parkinson's disease.Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by destruction of dopamine containing neurons in the substantia nigra pars compacta coupled with the formation of neuronal cytoplasmic inclusions known as Lewy bodies (Olanow and Tatton, 1999). Several lines of evidence have implicated failure of the ubiquitin proteasomal system (UPS) as central in the pathogenesis of PD, and a number of excellent, recent reviews have summarized the evidence linking defects in the UPS to both familial and sporadic PD

Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease

“…Aminochrome also induces protein degradation dysfunction by: i) impairing the proteasomal system in different in vitro models (Xiong et al, 2014; Zafar et al, 2006; Zhou and Lim, 2009); ii) inhibiting autophagy by preventing the adequate formation of microtubules required for the fusion of autophagic vacuoles and lysosomes in rat and human cell lines (Huenchuguala et al, 2014; Muñoz et al, 2012a; Paris et al, 2010); iii) inducing lysosomal dysfunction in human cell lines by affecting lysosomal acidification required for protein degradation inside these organelles (Huenchuguala et al, 2014). Aminochrome can induce oxidative stress when it is one-electron reduced by flavoenzymes to leukoaminochrome- o -semiquinone radical, which is extremely reactive with oxygen and auto-oxidizes immediately to aminochrome generating a redox cycling between aminochrome and leukoaminochrome- o -semiquinone radical, depleting both NADH or NADPH and oxygen, the latter being reduced to superoxide radical with consequent formation of hydroxyl radical, as demonstrated in rat cell lines experiments (Arriagada et al, 2004).…”

“…Interestingly, the products of DA oxidation (DA- o -quinone, aminochrome and 5,6-indolequinone) are directly involved in mitochondria dysfunction, protein degradation alteration, α-synuclein aggregation to neurotoxic oligomers and oxidative stress in dopaminergic neurons (Fig. 1, 2), suggesting that these o -quinones can play an important role in the degenerative process, resulting in the loss of SN dopaminergic neurons containing NM (Aguirre et al, 2012; Arriagada et al, 2004; Bisaglia et al, 2007; Dibenedetto et al, 2013; Hauser and Hastings, 2013; Huenchuguala et al, 2014; LaVoie et al, 2005; Martinez-Vicente et al, 2008; Muñoz et al, 2012a, 2015; Norris et al, 2005; Paris et al, 2010; Van Laar et al, 2009; Whitehead et al, 2001; Xiong et al, 2014; Xu et al, 1998; Zafar et al, 2006; Zhou and Lim, 2009). …”

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity

“…In a related work, DA was found to induce proteasome inhibition in PC12 cells, and this inhibition was attenuated by glutathione, MAO inhibitors, or a DA uptake inhibitor [22]. In addition, Zafar et al have demonstrated that DA quinone has the ability to inhibit proteasomal activity [13]. These findings suggest a possible role of proteasome inhibition in the toxicity induced by high levels of DA or its quinone in the cytosol.…”

“…In our previous reports, it has been shown that quinone formation plays an important role in a model of Parkinson's disease [8] and in methamphetamine (METH)-induced dopaminergic neurotoxicity [9]. Furthermore, several studies have clarified that the cytotoxicity of quinone formation is closely linked to other hypotheses of pathogenesis of Parkinson's disease and METH neurotoxicity such as mitochondrial dysfunction, inflammation and proteasome impairment [10][11][12][13]. Therefore, some molecules or reagents to prevent quinone formation or quench generated quinones would be potential therapeutic approaches against DA quinone-related dopaminergic neuronal disorders.…”

Molecular and Neurochemical Mechanisms Dopamine Oxidation To O-Quinones in Parkinson’s Disease Pathogenesis

“…(iii) Protein degradation dysfunction in which dopamine oxidation inactivates the proteasome system, although it is not clear which of the o-quinones is responsible for this inactivation [53]. However, aminochrome has been reported to inactivate the proteasome [108,109]. Aminochrome forms adducts with α-and β-tubulin preventing the formation of microtubules required for autophagosome fusion with lysosomes and induces lysosome dysfunction by increasing its internal pH [58,59,110].…”