Abstract:

Aging is well known to be the main risk factor for the neurodegenerative pathologies, in particular, Parkinson’s disease (PD) and Alzheimer’s disease (AD). In aging and in the diseases, similar changes in various hallmarks of neurodegeneration (lipofuscin accumulation,autophagia weakening, and disturbances in functions of mitochondria and lysosomes) were shown. Furthermore, dopaminergic system (DAS) involvement in mechanisms of aging, PD, and AD were revealed. Dopamine-producing neurons are predominantly concentrated in the substantia nigra (SN) and the ventral tegmental area (VTA). Dopamine (DA) terminals are  widespread in the brain, dominating in the hippocampus, prefrontal cortex, striatum, and olfactory bulbs.DA oxidization is well known to be accompanied by generation of various highly toxic compounds, in particular, reactive oxygen species (ROS).This is aggravated by auto-oxidization of DA with consequent accumulation of toxic DA-quinones (DA-Q) and other DA .Uncombined DA-Q is quickly neutralized by nucleophilic glutathione resulting in accumulation of 5-S-glutathionyl-DA, which, in turn, is transformed by enzymatic degradation into 5-S-cystenil-DA, one of the components of neuromelanin (NM). NM,predominantly accumulated in the SN, is able to bind free iron and,thus, to block both oxidative transformation of DA into its toxic forms and the ROS generation. These mechanisms allow the protection of neurons from the oxidative stress , thus, supporting normal functioning of DAS, in particular.