Advisory Committee Chair
Mathieu Lesort
Advisory Committee Members
Stephen A Watts
Peter J Detloff
Document Type
Thesis
Date of Award
2008
Degree Name by School
Master of Science (MS) College of Arts and Sciences
Abstract
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder. HD results from the genetic mutation that leads to an abnormally expanded polyglutamine (PolyQ) sequence within the protein. The disease is characterized by the accumulation of ubiquitinated mutant htt, suggesting dysfunction of the ubiquitin-proteasome system. Interestingly, there is data suggesting that the proteasome may not have the ability to efficiently degrade abnormally expanded polyglutamine. Furthermore, it has been demonstrated that there is proteasome impairment in HD and in cell models that expressed mutant htt, suggesting that mutant htt may cause dysfunction of the proteasome. Therefore, in this study, we further attempted to clarify the relationship between mutant htt and the UPS. To investigate the proteasome’s ability to degrade expanded polyglutamine sequence, we utilized proteasome targeted htt exon1 fusion proteins, containing a non-pathological (23Q) or pathological (65Q) polyglutamine sequence. Immunoblot analysis will allow us to monitor the degradation of the fusion proteins. Additionally, we determined if expanded polyglutamine has any affect on the catalytic activity of the proteasome by using the cleavage kinetics of fluorogenic substrates that are targeted to a specific catalytic site within the proteasome. The completion of this study enables characterization of the relationship between expanded polyglutamine sequences and the proteasome. We domonstrated the incomplete iii degradation of both non-pathological and pathological polyglutamine sequences and provided information suggesting that such proteins have a detrimental affect on the functionality of the proteasome.
Recommended Citation
Blaize, Marie Antoinette, "Degradation Of The Huntingtin Polyglutamine Domain By The Proteasome: Implication To Huntington’s Disease" (2008). All ETDs from UAB. 3556.
https://digitalcommons.library.uab.edu/etd-collection/3556
