Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

The Kinetics and Thermodynamics of Polyglutamine Aggregation

Landrum, Elizabeth C (2013) The Kinetics and Thermodynamics of Polyglutamine Aggregation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (3MB) | Preview


Protein misfolding as a result of polyglutamine (polyQ) repeat expansion plays a crucial role in the development a class of neurodegenerative disorders. These disorders are characterized by expansions in unique proteins, but share one common factor: polyQ repeat expansions beyond a pathological threshold, usually near 35 Glns. PolyQ containing peptides and proteins aggregate into amyloid-like fibrils, in both disease states and in vitro. While recent studies of simple polyQ aggregation have led to the development of a mechanism describing the fibril formation pathway, the kinetic and thermodynamic roles of even small modifications to the amino acid sequence are unclear. The goal of this work was to gain more specific information regarding the biophysical roles of terminal charge and Gln repeat length in the aggregation mechanism of simple polyQ peptides. We found that increases in both repeat length and attraction between terminal flanking sequences led to enhancements in fibril stability and spontaneous aggregation ability. In general, mutations in polyQ sequences that enhance their ability to assume a β-hairpin structure (the proposed building block of polyQ fibrils), and to associate with each other facilitate fibrillization through a nucleated polymerization pathway with a monomeric nucleus. The data discussed here have made significant contributions to our understanding of the basic aggregation properties of polyQ peptides, and have implications that can be directly translated to polyQ disease pathogenesis.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Landrum, Elizabeth Cecl20@pitt.eduECL20
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorWetzel, Ronaldrwetzel@pitt.eduRWETZEL
Committee MemberThibodeau, Patrickthibodea@pitt.eduTHIBODEA
Committee MemberZuckerman, Danielddmmzz@pitt.eduDDMMZZ
Committee MemberHorne, Sethhorne@pitt.eduHORNE
Date: 16 December 2013
Date Type: Publication
Defense Date: 6 December 2013
Approval Date: 16 December 2013
Submission Date: 16 December 2013
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 143
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: polyglutamine, polyQ, amyloid, aggregation, thermodynamics, fibrils
Date Deposited: 16 Dec 2013 20:32
Last Modified: 15 Nov 2016 14:16


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item