Journal
NEUROBIOLOGY OF DISEASE
Volume 73, Issue -, Pages 204-212Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2014.10.002
Keywords
PARK2; Neurotoxicty; Environmental risk factors; Parkinson's disease; Copper
Categories
Funding
- Vanderbilt Ingram Cancer Center [P30CA68485]
- Vanderbilt Digestive Disease Research Center [DK058404]
- Doris Duke Charitable Foundation
- Hazinski-Turner Award (KCE)
- Peterson Foundation for Parkinson's (ABB)
- NIH/NIGMS [5P01 GM08535403, 132 GM07347]
- NIH/NINDS [1 RO1 NS078289, K02NS057666, P3OHD15052]
- NIH/NIEHS [5P30 ES000267, ES016931, ES016931-02S1]
Ask authors/readers for more resources
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 PARIC2 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 PARIC2 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. (C) 2015 Elsevier Inc All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available