title: PARK2 patient neuroprogenitors show increased mitochondrial sensitivity to copper.
abstract: Poorly-defined interactions between environmental and genetic risk factors underlie Parkinson's disease (PD) etiology. Here we tested the hypothesis that human stem cell derived forebrain neuroprogenitors from patients with known familial risk for early onset PD will exhibit enhanced sensitivity to PD environmental risk factors compared to healthy control subjects without a family history of PD. Two male siblings (SM and PM) with biallelic loss-of-function mutations in PARK2 were identified. Human induced pluripotent stem cells (hiPSCs) from SM, PM, and four control subjects with no known family histories of PD or related neurodegenerative diseases were utilized. We tested the hypothesis that hiPSC-derived neuroprogenitors from patients with PARK2 mutations would show heightened cell death, mitochondrial dysfunction, and reactive oxygen species generation compared to control cells as a result of exposure to heavy metals (PD environmental risk factors). We report that PARK2 mutant neuroprogenitors showed increased cytotoxicity with copper (Cu) and cadmium (Cd) exposure but not manganese (Mn) or methyl mercury (MeHg) relative to control neuroprogenitors. PARK2 mutant neuroprogenitors also showed a substantial increase in mitochondrial fragmentation, initial ROS generation, and loss of mitochondrial membrane potential following Cu exposure. Our data substantiate Cu exposure as an environmental risk factor for PD. Furthermore, we report a shift in the lowest observable effect level (LOEL) for greater sensitivity to Cu-dependent mitochondrial dysfunction in patients SM and PM relative to controls, correlating with their increased genetic risk for PD.
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: Asad A
authors.initials: AA
authors.lastname: Aboud
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tidball
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Kumar
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Brain Institute, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Center in Molecular Toxicology, Nashville, TN, USA.
authors.forename: M Diana
authors.initials: MD
authors.lastname: Neely
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA.
authors.forename: Bingying
authors.initials: B
authors.lastname: Han
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Brain Institute, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Center for Stem Cell Biology, Nashville, TN, USA.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ess
authors.affiliation: Vanderbilt University Medical Center, Vanderbilt Center for Stem Cell Biology, Nashville, TN, USA; Vanderbilt University Medical Center, Research Medicine, Veterans Affairs TVHS, Cardiovascular Medicine Division, Nashville, TN, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.affiliation: University of North Carolina-Greensboro, Dept. of Nutrition, Greensboro, NC 27402-6107, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Erikson
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Brain Institute, Nashville, TN, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hedera
authors.affiliation: Vanderbilt University Medical Center, Dept. of Neurology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Kennedy Center, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Brain Institute, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Center in Molecular Toxicology, Nashville, TN, USA; Vanderbilt University Medical Center, Vanderbilt Center for Stem Cell Biology, Nashville, TN, USA. Electronic address: aaron.bowman@vanderbilt.edu.
authors.forename: Aaron B
authors.initials: AB
authors.lastname: Bowman
mesh_terms: D000328:Adult; D002104:Cadmium / Q000378:metabolism*; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D008297:Male; D008345:Manganese / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008767:Methylmercury Compounds / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D044767:Ubiquitin-Protein Ligases
chemical_list: D008767:Methylmercury Compounds; D002104:Cadmium; D008345:Manganese; D003300:Copper; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: Copper; Environmental risk factors; Neurotoxicty; PARK2; Parkinson's disease