Date of Graduation


Document Type


Degree Type



Eberly College of Arts and Sciences



Committee Chair

Justin Legleiter

Committee Member

John Blakely Mertz

Committee Member

Visvanathan Ramamurthy

Committee Member

Kenneth Showalter

Committee Member

Stephen Valentine


Huntington’s Disease (HD) is a genetic, neurodegenerative disease characterized by an abnormal polyglutamine (polyQ) expansion in the first exon of the huntingtin protein (htt). The polyQ domain facilitates aggregation and initiates the formation of a diverse collection of aggregate species, including fibrils, oligomers and annular aggregates. The first 17 amino acids of htt (Nt17) directly flank the polyQ domain and is a key factor in htt’s association to membranous structures. In addition to Nt17 being an amphipathic αhelix, it also promotes aggregation through self-association and contains numerous posttranslational modifications (PTMs) that can modulate toxicity and subcellular localization. For in depth understanding of these mechanisms, particularly in the presence of lipid membrane surfaces, the PTM phosphorylation and macromolecular crowders found in subcellular environments were explored. Through the application of phosphomimetic mutations of htt to a variety of lipid systems, lipid-specific impacts of electrostatic interactions involved in htt/lipid interactions were elucidated. Cytosolic conditions mimicked through the addition of macromolecular crowders and htt were evaluated at both solid/liquid and membrane/liquid interfaces, with each crowder having a distinct effect on htt aggregation. The results presented here aid in the understanding of the multi-faceted nature of htt aggregation in the presence of cellular and subcellular surfaces.