Mishra, Rakesh
(2012)
BIOPHYSICAL MECHANISMS OF AMYLOID NUCLEATION
IN POLYGLUTAMINE CONTAINING HTT FRAGMENTS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/12296 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}