title: Correlation between the biochemical pathways altered by mutated parkinson-related genes and chronic exposure to manganese.
abstract: The studies presented in this review attempt to describe the operative properties of the genes involved in generation of early and late onset of Parkinson's disease or Parkinson-like disorders and how mutation in these genes relate to onset of manganism. These include the genes α-synuclein, parkin, PINK1, DJ-1, ATP13A2, and SLC30A10 which are associated with early-onset of Parkinson's as well as those genes linked with late onset of the disorder which include, LRRK2 and VPS35. Since mutations in these genes and excess Mn potentially disrupt similar cellular processes within the basal ganglia, it is reasonable to hypothesize that the expressed symptoms of Parkinson's disease may overlap with that of manganese (Mn) toxicity. There appears to be four common processes linking the two disorders, as mutations in genes associated with Parkinsonism initiate similar adverse biological reactions acknowledged to stimulate Mn-induced dopaminergic cell death including; (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 processes provoked by mutations in these genes in concert with the biological disturbances produced by Mn, most likely, act in synchrony to contribute to the severity, characteristics and onset of both disorders.
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY 14214, United States. Electronic address: jaroth@buffalo.edu.
authors.forename: Jerome A
authors.initials: JA
authors.lastname: Roth
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics; D004781:Environmental Exposure; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008345:Manganese / Q000633:toxicity*; D051379:Mice; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000235:genetics; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics; D000075703:Zinc Transporter 8; D051844:alpha-Synuclein / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
chemical_list: D027682:Cation Transport Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008345:Manganese; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D006180:Proton-Translocating ATPases; D044767:Ubiquitin-Protein Ligases; D033921:Vesicular Transport Proteins; D000075703:Zinc Transporter 8; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C514983:ATP13A2 protein, human; C492522:SLC30A8 protein, human; C419573:VPS35 protein, human; C111567:parkin protein; C495280:LRRK2 protein, human; C105131:PARK7 protein, human
keywords: Gene markers; Manganese; Manganism; Parkinson's disease