Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

Abstract

Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best‐studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox‐active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post‐translational protein modification. Thus, protein–quinone modification is a heterogeneous process involving multiple DA‐derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins.

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

“…However, hTyr‐overexpressing rodents showed no significant accumulation of oxidized dopamine species, either preceding or concomitant with neuronal dysfunction/degeneration . In fact, the significant accumulation of such potentially toxic species in these animals was actually prevented by their continuous conversion into neuromelanin, this being consistent with a putative protective antioxidant role of neuromelanin synthesis . Further arguing against a major pathogenic contribution of dopamine‐mediated toxicity in hTyr‐overexpressing rodents, it has been recently reported by 2 independent groups that dopamine‐induced toxicity in rodents, either by chronic l ‐dopa treatment or by enhancing TH activity, is only observed in animals displaying additional PD‐related alterations, such as DJ‐1 deficiency or overexpression of PD‐linked A53T mutant α‐synuclein, but not in regular wild‐type animals (as opposed to the PD phenotype observed in wild‐type rodents overexpressing hTyr).…”

“…In fact, neuromelanin synthesis is regarded as a protective antioxidant mechanism to remove potentially toxic oxidized dopamine species, such as quinones and semiquinones, by their conversion into neuromelanin . However, although peripheral melanogenesis occurring within specialized cells (ie, melanocytes) is known to result from an enzymatically driven biosynthetic pathway in which tyrosinase is the key, rate‐limiting enzyme, it is widely assumed that neuromelanin is instead produced by spontaneous nonenzymatic dopamine auto‐oxidation . Several observations argue, however, against the latter concept.…”

“…43 In fact, the significant accumulation of such potentially toxic species in these animals was actually prevented by their continuous conversion into neuromelanin, 43 this being consistent with a putative protective antioxidant role of neuromelanin synthesis. 31 Further arguing against a major pathogenic contribution of dopamine-mediated toxicity in hTyr-overexpressing rodents, it has been recently reported by 2 independent groups that dopamine-induced toxicity in rodents, either by chronic L-dopa treatment 35 or by enhancing TH activity, 37 is only observed in animals displaying additional PD-related alterations, such as DJ-1 deficiency 35 or overexpression of PD-linked A53T mutant α-synuclein, 37 but not in regular wild-type animals 35,37 (as opposed to the PD phenotype observed in wild-type rodents overexpressing hTyr 43 ). Indeed, although high concentrations of dopamine can be acutely toxic, mostly in vitro, 11 the chronic enhancement of dopamine levels does not cause dopaminergic nerve terminal or cell body loss in vivo, [35][36][37] probably because of compensatory protective mechanisms.…”

“…29 However, although peripheral melanogenesis occurring within specialized cells (ie, melanocytes) is known to result from an enzymatically driven biosynthetic pathway in which tyrosinase is the key, rate-limiting enzyme, 30 it is widely assumed that neuromelanin is instead produced by spontaneous nonenzymatic dopamine auto-oxidation. 31 Several observations argue, however, against the latter concept. For instance, the distribution of neuromelanin does not fully match that of the dopamine-producing enzyme tyrosine hydroxylase (TH), with many dopamine and noradrenergic neurons completely lacking neuromelanin.…”

“…The oxidation of dopamine to form neuromelanin generates many o-quinones, which can be potentially toxic to neurons 31 (Fig. 3).…”