Selective dopaminergic neurotoxicity modulated by inherent cell-type specific neurobiology

Parkinson’s disease (PD) is a debilitating neurodegenerative disease affecting millions of individuals worldwide. Hallmark features of PD pathology are the formation of Lewy bodies in neuromelanin-containing dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc), and the subsequent irreversible death of these neurons. Although genetic risk factors have been identified, around 90 % of PD cases are sporadic and likely caused by environmental exposures and gene-environment interaction. Mechanistic studies have identified a variety of chemical PD risk factors. PD neuropathology occurs throughout the brain and peripheral nervous system, but it is the loss of DAergic neurons in the SNpc that produce many of the cardinal motor symptoms. Toxicology studies have found specifically the DAergic neuron population of the SNpc exhibit heightened sensitivity to highly variable chemical insults (both in terms of chemical structure and mechanism of neurotoxic action). Thus, it has become clear that the inherent neurobiology of nigral DAergic neurons likely underlies much of this neurotoxic response to broad insults. This review focuses on inherent neurobiology of nigral DAergic neurons and how such neurobiology impacts the primary mechanism of neurotoxicity. While interactions with a variety of other cell types are important in disease pathogenesis, understanding how inherent DAergic biology contributes to selective sensitivity and primary mechanisms of neurotoxicity is critical to advancing the field. Specifically, key biological features of DAergic neurons that increase neurotoxicant susceptibility.