ABSTRACT
Huntingtons disease (HD) is an autosomal dominant neurodegenerative disorder predominantly afflicting the striatum. It is clear that an expansion of a glutamine encoding CAG triplet-repeat in the Huntingtin (HTT) gene causes HD. However, the molecular basis of the selective pathology has not been elucidated. The wild-type HD protein has recently been discovered to play a role in iron homeostasis and associates with copper. Like HD, copper (Cu), iron (Fe), and manganese (Mn) neurotoxicity is associated with basal ganglia dysfunction. Environmental overexposure to the essential metal Mn leads to accumulation of Mn in the basal ganglia and a parkinsonian-like condition called manganism. Recognizing the pathophysiological similarities between HD and the neurotoxicity of these metals, we hypothesized that metals may exhibit gene-environment interactions with the HD gene, HTT.
To determine the contribution of specific physiological and pathological processes to selective neuropathology in HD, we tested various metals that influence similar neuronal populations to identify modifications in cellular functions of the normal or disease-causing HD protein. Using a cellular model of HD, we have found that expression of the mutant HTT protein induces a resistance specifically to Mn toxicity. To understand the cellular basis of this phenotype, we investigated the possibility that HTT may alter Mn transport. We found that net accumulation of Mn is substantially decreased in cells expressing mutant HTT under standard culture conditions and after Mn exposure. Given previous reports linking HTT with iron homeostasis, we examined a role for Fe transport in this phenotype. Our data indicate that functional differences in Fe homeostasis only partially contribute to the Mn transport deficit. Assessment of other known Mn transporters (e.g. Divalent metal transporter 1 (DMT1) and the Zip8 family) failed to reveal a significant contribution for these pathways. To corroborate the Mn transport defects in vivo, we exposed the YAC128Q mouse model of HD to Mn and found that mutant HTT selectively impairs net Mn transport in the striatum, the brain region most vulnerable to HD. Therefore, we conclude that mutant HTT alters Mn homeostatic control and has the potential to contribute to selective degeneration.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-03292010-105231 |
| Date | 10 April 2010 |
| Creators | Williams, Brooke Blairanne |
| Contributors | Roger Colbran, Aaron Bowman, Michael Aschner, Douglas Mortlock |
| 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-03292010-105231/ |
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