Parkinsons disease (PD) is a neurodegenerative, motor disorder that is characterized by selective dopaminergic cell loss in the substantia nigra pars compacta. About 10-20% of PD cases have genetic causes; nonetheless, the idiopathic nature of the majority of PD cases calls for the contribution of environmental factors in its etiology. One such factor is the essential trace element manganese (Mn); excessive exposure can result in manganism, which shares similarities with both PD symptomatology and molecular signatures. This overlap warrants investigation into whether a particular genetic risk factor increases susceptibility of DAergic neurons to environmental risk factors. Using the Caenorhabditis elegans (C. elegans) model system, loss of two genes associated with an early-onset, autosomal recessive form of PD, pdr-1/parkin and djr-1/dj-1, results in enhanced Mn accumulation and oxidative stress that can be rescued by the expression of another PD-associated protein known as α-Syn (alpha-synuclein), a protein found aggregated in some PD cases. Moreover, the loss of pdr-1/parkin results in increased mRNA expression of a Mn export gene known as ferroportin (fpn-1). As overexpression of this exporter can rescue pdr-1/parkin mutant phenotypes, these studies support the role of abnormal metal homeostasis as a consequence of genetic mutations associated with early-onset PD.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03152015-170233 |
| Date | 26 March 2015 |
| Creators | Chakraborty, Sudipta |
| Contributors | Michael Aschner, Aaron Bowman, William Valentine, Keith Erikson |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-03152015-170233/ |
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