Chapter 9: Mutual Neurotoxic Mechanisms Controlling Manganism and Parkisonism

The studies presented in this review attempt to characterize the functional properties of genes identified as producing Parkinson's disease or Parkinson-like disorders and how mutation of these genes correlate, from a mechanistic perspective, to provocation of manganese (Mn) toxicity. These include genes associated with early-onset of Parkinson's disease, which are comprised of parkin, DJ-1, PINK, and ATP13A2, as well as those associated with late onset of the disorder, which include LRRK2 and VPS35. Because both neurological disorders are associated with altered function and output of the basal ganglia, it is not surprising that symptoms of Parkinson's disease often overlap with that of Mn toxicity. There appears to be four common threads linking the two disorders because mutations in genes associated with early and late onset of Parkinsonism produce similar adverse biological responses acknowledged to provoke Mn-induced dopaminergic cell death: (1) disruption of mitochondrial function leading to oxidative stress; (2) abnormalities in vesicle processing; (3) altered proteasomal and lysosomal protein degradation; and (4) α-synuclein aggregation. The mutual neurotoxic actions of these genes, along with that of Mn, most likely act in synchrony to contribute to the severity, characteristics, and onset of both disorders.