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http://hdl.handle.net/11375/15344
Title: | Using Förster Resonance Energy Transfer (FRET) To Define the Conformational Changes of Huntingtin at the Clinical Threshold for Huntington’s Disease |
Authors: | Caron, Nicholas S. |
Advisor: | Truant, Ray David Andrews, Jon Draper |
Department: | Biochemistry and Biomedical Sciences |
Keywords: | Huntington's disease;huntingtin;biosensor;FRET;Medical Cell Biology;Medical Molecular Biology;Nervous System Diseases;Medical Cell Biology |
Publication Date: | Apr-2014 |
Abstract: | <p>Huntington’s disease (HD) is a progressive, neurodegenerative disorder that leads to the selective loss of neurons in the striatum and the cerebral cortex. HD is caused by a CAG trinucleotide repeat expansion beyond the normal length in the <em>IT15 </em>(<em>Htt</em>) gene. The CAG stretch codes for an elongated polyglutamine tract within the amino‐terminus of the huntingtin protein. Polyglutamine tracts with lengths exceeding 37 repeats cause HD whereas repeat lengths below do not. This phenomenon has plagued the HD community since the discovery of the gene in 1993. In this thesis, we sought to elucidate the molecular mechanism by which huntingtin becomes toxic at polyglutamine lengths above 37. Using Förster resonance energy transfer (FRET) techniques, we describe an intramolecular proximity between the first 17 residues (N17) and the proline-rich regions, which flank the polyglutamine tract of huntingtin. We report that we can precisely measure differences between the conformations adopted by the huntingtin protein with polyglutamine tracts below and above the pathogenic repeat threshold of 37 repeats. Our data supports the hypothesis that polyglutamine tracts below the pathogenic threshold can act as a flexible hinge allowing the N17 domain to freely fold back upon huntingtin and come into close 3D proximity with the polyproline region. This flexibility is lost in polyglutamine tracts with >37 repeats resulting in a diminished spatial proximity between N17 and the polyproline domain.</p> |
URI: | http://hdl.handle.net/11375/15344 |
Identifier: | opendissertations/8880 9959 5429784 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
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fulltext.pdf | 4.7 MB | Adobe PDF | View/Open |
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