Role of genetic manipulations in manganese-induced dopaminergic neurodegeneration in C. elegans

• Applicant: Professorin Dr. Julia Bornhorst
• Subject Area: Food Chemistry
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234632908

An occupational and dietary overexposure to the essential trace element manganese (Mn) has been shown to cause neuropsychiatric and neuromotoric symptoms similar to Parkinson disease (PD). To date modes of neurotoxic action of Mn are still to be elucidated, but are thought to be strongly related to oxidative stress, mitochondrial impairment and protein aggregation. This study is designed to assess possible interactions between Mn and PD-associated proteins in the genetically amenable nematode Caenorhabditis elegans (C. elegans). Therefore worms will be generated with a genetic manipulation of the PD-associated genes DJ-1 and PINK1. The respective proteins are known to participate in the oxidative stress response and their inhibition enhances the formation of reactive oxygen species, protein aggregation and dopaminergic neurodegeneration. Next it will be studied if knockdown or loss-of-function mutations combined with an excessive Mn exposure hasten the development of PD or if an overexpression protects the worms against oxidant-induced dopaminergic neurodegeneration mediated by Mn. Since PINK1 is also involved in DNA damage response and Mn has been shown before to alter DNA damage related signaling reactions, this work will additionally investigate the DNA damage response of the above mentioned genetically manipulated worm lines in the presence of Mn. Understanding gene/environment interactions in the C. elegans model will provide critical insights in the mechanisms of Mn-induced neurotoxicity and PD and the development of novel therapeutic strategies to protect against dopaminergic neurodegeneration.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Michael Aschner, Ph.D.