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Mishra, Rakesh (2012) BIOPHYSICAL MECHANISMS OF AMYLOID NUCLEATION IN POLYGLUTAMINE CONTAINING HTT FRAGMENTS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Huntington’s disease, one of nine CAG repeat diseases, is triggered by an expansion of a
polyglutamine (polyQ) tract in the huntingtin (htt) protein. The aggregation of the first exon of
htt (and fragments thereof) is believed to be intricately tied to the pathology of Huntington’s
disease. Recent work in the field has identified a crucial role for the first seventeen residues of
huntingtin (httNT), implicated in a wide range of cellular processes, in modulating the
aggregation of htt both in vitro and in vivo. The focus of this work has been to identify the
biophysical mechanisms underlying httNT mediated aggregation. Using a combination of
experimental and computational techniques, we demonstrate the crucial role of the amphipathic
helical propensity of httNT in mediating initial oligomerization of htt fragments and by extension,
the aggregation of polyQ containing htt fragments. We also assess the effect of post-translational
modifications (PTMs) within the httNT sequence on the aggregation of htt fragments, providing a
biophysical perspective to the role that these PTMs might play in HD pathology. Finally, in
addition to the role of httNT in directing the initial oligomerization of htt fragments, we also
provide evidence for a role of polyQ expansion in stabilizing htt fragment oligomers. Overall, the
results of these studies not only add to our understanding of htt exon-1 aggregation but also
provide additional clues for the ultimate role that aggregation plays in HD pathology.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairWetzel, Ronaldrwetzel@pitt.eduRWETZEL
Bahar, Ivetbahar@pitt.eduBAHAR
Van Der Wel, Patrickpvdwel@pitt.eduPVDWEL
Thibodeau, Patrickthibodea@pitt.eduTHIBODEA
Klein-Seetharaman, Judithjks33@pitt.eduJKS33
Date: 6 June 2012
Date Type: Publication
Defense Date: 23 May 2012
Approval Date: 6 June 2012
Submission Date: 5 June 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 225
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Biophysics and Structural Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Amyloid, Huntington's disease, protein aggregation, polyglutamine, huntingtin
Date Deposited: 06 Jun 2012 12:46
Last Modified: 15 Nov 2016 13:58


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