Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects.

Aboud AA, Tidball AM, Kumar KK, Neely MD, Ess KC, Erikson KM, Bowman AB
Neurotoxicology. 2012 33 (6): 1443-1449

PMID: 23099318 · PMCID: PMC3518601 · DOI:10.1016/j.neuro.2012.10.009

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

MeSH Terms (25)

Biosensing Techniques Case-Control Studies Cell Line Cell Survival Chlorides Dose-Response Relationship, Drug Environmental Pollutants Gene-Environment Interaction Genetic Predisposition to Disease Humans Induced Pluripotent Stem Cells Manganese Compounds Manganese Poisoning Membrane Potential, Mitochondrial Mitochondria Mutation Neural Stem Cells Neurologic Examination Parkinson Disease Parkinson Disease, Secondary Phenotype Reactive Oxygen Species Risk Factors Time Factors Ubiquitin-Protein Ligases

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