1. Exposure to Mitochondrial Genotoxins and Dopaminergic Neurodegeneration in Caenorhabditis elegans
- Author
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Sara Guckian Kosmaczewski, Andrew E. Arrant, Derek D. Cyr, Maxwell C.K. Leung, Claudia P. Gonzalez-Hunt, Ian T. Ryde, Madeline G. McKeever, Marc Hammarlund, Joel N. Meyer, Rakesh Bodhicharla, and Kathleen M. Margillo
- Subjects
Nematoda ,Dopamine ,Dopamine Agents ,lcsh:Medicine ,Mitochondrion ,Toxicology ,Biochemistry ,chemistry.chemical_compound ,Neurobiology of Disease and Regeneration ,Medicine and Health Sciences ,lcsh:Science ,Caenorhabditis elegans ,Energy-Producing Organelles ,Genetics ,Multidisciplinary ,Movement Disorders ,biology ,Neurodegeneration ,Dopaminergic ,Neurodegenerative Diseases ,Parkinson Disease ,Animal Models ,Mitochondrial DNA ,Cell biology ,Nuclear DNA ,Mitochondria ,Neurology ,Cellular Structures and Organelles ,Oxidopamine ,Research Article ,Neurotoxicology ,Paraquat ,DNA damage ,Forms of DNA ,Genetic Toxicology ,Neurotoxins ,Bioenergetics ,Research and Analysis Methods ,DNA, Mitochondrial ,Model Organisms ,Adrenergic Agents ,medicine ,Animals ,Biology and life sciences ,Dopaminergic Neurons ,lcsh:R ,Organisms ,DNA ,Cell Biology ,biology.organism_classification ,medicine.disease ,Invertebrates ,chemistry ,Nerve Degeneration ,Caenorhabditis ,lcsh:Q ,Mitochondrial Genetics ,Mutagens - Abstract
Neurodegeneration has been correlated with mitochondrial DNA (mtDNA) damage and exposure to environmental toxins, but causation is unclear. We investigated the ability of several known environmental genotoxins and neurotoxins to cause mtDNA damage, mtDNA depletion, and neurodegeneration in Caenorhabditis elegans. We found that paraquat, cadmium chloride and aflatoxin B1 caused more mitochondrial than nuclear DNA damage, and paraquat and aflatoxin B1 also caused dopaminergic neurodegeneration. 6-hydroxydopamine (6-OHDA) caused similar levels of mitochondrial and nuclear DNA damage. To further test whether the neurodegeneration could be attributed to the observed mtDNA damage, C. elegans were exposed to repeated low-dose ultraviolet C radiation (UVC) that resulted in persistent mtDNA damage; this exposure also resulted in dopaminergic neurodegeneration. Damage to GABAergic neurons and pharyngeal muscle cells was not detected. We also found that fasting at the first larval stage was protective in dopaminergic neurons against 6-OHDA-induced neurodegeneration. Finally, we found that dopaminergic neurons in C. elegans are capable of regeneration after laser surgery. Our findings are consistent with a causal role for mitochondrial DNA damage in neurodegeneration, but also support non mtDNA-mediated mechanisms.
- Published
- 2014