Author ORCID Identifier

https://orcid.org/0009-0001-9318-3920

Semester

Spring

Date of Graduation

2024

Document Type

Thesis

Degree Type

MS

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Justin Legleiter

Committee Member

Hacer Karatas Bristow

Committee Member

Stephen Valentine

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an abnormally long CAG repeat in the huntingtin gene. This results in an expanded polyglutamine (polyQ) domain in the huntingtin protein (htt) that directly leads to self-assembly of huntingtin (htt) into a variety of aggregate species that underlie cellular toxicity. Interaction of protein aggregates with a variety of lipid membranes has been linked to disease pathology. Here, the ability of a small molecule S(+)-propylnorapomorphine (NM) hydrochloride to modulate htt-exon1(46Q) aggregation and interactions with lipid membranes was determined. ThT assays were performed to quantify fibril formation of htt in the presence and absence of lipid vesicles. As the concentration of NM increases, the formation of fibrils decreases. In addition, atomic force microscopy (AFM) was used to directly monitor the formation of aggregates containing doses of NM both in the presence and absence of lipid vesicles. In situ AFM was performed on supported liquid bilayers exposed to huntingtin and drug to monitor membrane damage. Morphological changes in aggregate height and volume are observed in the presence of the small molecule. NM reduced fibril formation and reduced the ability of htt to bind membranes.


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