Molecular and neurochemical mechanisms dopamine oxidation to O-Quinones in parkinson’s disease pathogenesis

Abstract

Four decades after L-dopa was introduced as a therapy for Parkinson’s disease, it is still the gold standard for Parkinson’s pharmacological treatment because no new drug has been discovered. This is due to the ambiguity regarding the molecular mechanisms responsible for the degeneration of dopaminergic neurons containing neuromelanin in the substantia nigra, which induces the motor symptoms of Parkinson’s disease. The question is to identify the mechanisms underlying the neurodegenerative process of Parkinson’s disease initiated years before the motor symptoms are evident, through pre-motor symptoms. The possible role of an exogenous environmental neurotoxin has been proposed. However, MPTP generates severe Parkinsonism in just 3 days, in contrast with idiopathic Parkinson’s disease, which occurs after years of slow degeneration. The discovery of proteins (such as alpha synuclein and parkin) associated with the familial form of the disease opened new lines of basic research, resulting in a general agreement that five mechanisms are involved in the degeneration of dopaminergic neurons containing neuromelanin: protein degradation dysfunction, mitochondrial dysfunction, alpha synuclein aggregation, oxidative stress and neuroinflammation. Dopamine oxidation sequentially generates dopamine o-quinone, aminochrome, 5,6-indolequinone and finally, neuromelanin. These o-quinones have been reported to be directly involved in four of the five above-mentioned mechanisms: protein degradation dysfunction, mitochondria dysfunction, alpha synuclein aggregation and oxidative stress. This suggests that dopamine oxidation to o-quinone may play a role in the degeneration of the dopaminergic neurons of the nigrostriatal system in Parkinson’s disease.