Neurotoxicity of Metals

W. Michael Caudle

Parkinsonism is comprised of a host of neurological disorders with an underlying clinical feature of movement disorder, which includes many shared features of bradykinesia, tremor, and rigidity. These clinical outcomes occur subsequent to pathological deficits focused on degeneration or dysfunction of the nigrostriatal dopamine system and accompanying pathological inclusions of alpha-synuclein and tau. The heterogeneity of parkinsonism is equally matched with the complex etiology of this syndrome. While a small percentage can be attributed to genetic alterations, the majority arise from an environmental exposure, generally composed of pesticides, industrial compounds, as well as metals. Of these, metals have received significant attention given their propensity to accumulate in the basal ganglia and participate in neurotoxic cascades, through the generation of reactive oxygen species as well as their pathogenic interaction with intracellular targets in the dopamine neuron. The association between metals and parkinsonism is of critical concern to subsets of the population that are occupationally exposed to metals, both through current practices, such as mining, and emerging settings, like E-waste and the manufacture of metal nanoparticles. This review will explore our current understanding of the molecular and pathological targets that mediate metal neurotoxicity and lead to parkinsonism and will highlight areas of critical research interests that need to be addressed.