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Title page for ETD etd-03152015-170233


Type of Document Dissertation
Author Chakraborty, Sudipta
URN etd-03152015-170233
Title Gene-Environment Interactions Between Manganese Toxicity and Early-Onset Parkinson's Disease Genes
Degree PhD
Department Neuroscience
Advisory Committee
Advisor Name Title
William Valentine Committee Chair
Aaron Bowman Committee Member
Keith Erikson Committee Member
Michael Aschner Committee Member
Keywords
  • Parkinsons disease
  • manganese
  • neurotoxicology
  • C. elegans
  • parkin
  • pink1
  • dj1
  • ferroportin
  • DMT1
  • oxidative stress
Date of Defense 2015-01-16
Availability unrestricted
Abstract
Parkinson’s 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.
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