Dopaminergic neuron metabolism: relevance for understanding Parkinson's disease

BackgroundDopaminergic neurons from the substantia nigra pars compacta (SNc) have a higher susceptibility to aging-related degeneration, compared to midbrain dopaminergic cells present in the ventral tegmental area (VTA); the death of dopamine neurons in the SNc results in Parkinson<acute accent>s disease (PD). In addition to increased loss by aging, dopaminergic neurons from the SNc are more prone to cell death when exposed to genetic or environmental factors, that either interfere with mitochondrial function, or cause an increase of oxidative stress. The oxidation of dopamine is a contributing source of reactive oxygen species (ROS), but this production is not enough to explain the differences in susceptibility to degeneration between SNc and VTA neurons.Aim of reviewIn this review we aim to highlight the intrinsic differences between SNc and VTA dopamine neurons, in terms of gene expression, calcium oscillations, bioenergetics, and ROS responses. Also, to describe the changes in the pentose phosphate pathway and the induction of apoptosis in SNc neurons during aging, as related to the development of PD.Key scientific concepts of reviewRecent work showed that neurons from the SNc possess intrinsic characteristics that result in metabolic differences, related to their intricate morphology, that render them more susceptible to degeneration. In particular, these neurons have an elevated basal energy metabolism, that is required to fulfill the demands of the constant firing of action potentials, but at the same time, is associated to higher ROS production, compared to VTA cells. Finally, we discuss how mutations related to PD affect metabolic pathways, and the related mechanisms, as revealed by metabolomics.