title: Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects.
abstract: Manganese (Mn) is an environmental risk factor for Parkinson's disease (PD). Recessive inheritance of PARK2 mutations is strongly associated with early onset PD (EOPD). It is widely assumed that the influence of PD environmental risk factors may be enhanced by the presence of PD genetic risk factors in the genetic background of individuals. However, such interactions may be difficult to predict owing to the complexities of genetic and environmental interactions. Here we examine the potential of human induced pluripotent stem (iPS) cell-derived early neural progenitor cells (NPCs) to model differences in Mn neurotoxicity between a control subject (CA) with no known PD genetic risk factors and a subject (SM) with biallelic loss-of-function mutations in PARK2 and family history of PD but no evidence of PD by neurological exam. Human iPS cells were generated from primary dermal fibroblasts of both subjects. We assessed several outcome measures associated with Mn toxicity and PD. No difference in sensitivity to Mn cytotoxicity or mitochondrial fragmentation was observed between SM and CA NPCs. However, we found that Mn exposure was associated with significantly higher reactive oxygen species (ROS) generation in SM compared to CA NPCs despite significantly less intracellular Mn accumulation. Thus, this report offers the first example of human subject-specific differences in PD-relevant environmental health related phenotypes that are consistent with pathogenic interactions between known genetic and environmental risk factors for PD.
authors.affiliation: Vanderbilt University Medical Center, Department of Neurology and Vanderbilt Kennedy Center, Nashville, TN 37232-8552, USA.
authors.forename: Asad A
authors.initials: AA
authors.lastname: Aboud
authors.affiliation: Vanderbilt University Medical Center, Department of Neurology and Vanderbilt Kennedy Center, Nashville, TN 37232-8552, USA; Vanderbilt Brain Institute, Nashville, TN 37232-8552, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tidball
authors.affiliation: Vanderbilt University Medical Center, Department of Neurology and Vanderbilt Kennedy Center, Nashville, TN 37232-8552, USA; Vanderbilt Brain Institute, Nashville, TN 37232-8552, USA; Vanderbilt Medical Scientist Training Program, Nashville, TN 37232-8552, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Kumar
authors.affiliation: Vanderbilt University Medical Center, Department of Neurology and Vanderbilt Kennedy Center, Nashville, TN 37232-8552, USA; Vanderbilt Brain Institute, Nashville, TN 37232-8552, USA.
authors.forename: M Diana
authors.initials: MD
authors.lastname: Neely
authors.affiliation: Vanderbilt University Medical Center, Department of Neurology and Vanderbilt Kennedy Center, Nashville, TN 37232-8552, USA; Vanderbilt Brain Institute, Nashville, TN 37232-8552, USA; Vanderbilt Center for Stem Cell Biology and The Department of Pediatrics, Nashville, TN 37232-8552, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ess
authors.affiliation: University of North Carolina-Greensboro, Nutrition Department, Greensboro, NC 27402-6107, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Erikson
authors.affiliation: Vanderbilt University Medical Center, Department of Neurology and Vanderbilt Kennedy Center, Nashville, TN 37232-8552, USA; Vanderbilt Brain Institute, Nashville, TN 37232-8552, USA; Vanderbilt Center for Stem Cell Biology and The Department of Pediatrics, Nashville, TN 37232-8552, USA; Vanderbilt Center in Molecular Toxicology, Vanderbilt University, Nashville, TN 37232-8552, USA. Electronic address: aaron.bowman@vanderbilt.edu.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
mesh_terms: D015374:Biosensing Techniques; D016022:Case-Control Studies; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017895:Manganese Compounds / Q000378:metabolism; D020149:Manganese Poisoning / Q000235:genetics* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009460:Neurologic Examination; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D013997:Time Factors; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D002712:Chlorides; D004785:Environmental Pollutants; D017895:Manganese Compounds; D017382:Reactive Oxygen Species; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C025340:manganese chloride