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Dissertation/Thesis Abstract

Evolutionarily Conserved Function of Huntingtin in Cellular Dynamics Related to Cell Adhesion and the Cytoskeleton
by Thompson, Morgan Nicole, Ph.D., Harvard University, 2013, 140; 3553491
Abstract (Summary)

Huntington's disease (HD) is a rare, dominantly inherited neurodegenerative disorder characterized by progressive chorea, emotional and behavioral disturbances, and cognitive decline. The single, causative mutation is an expanded trinucleotide repeat of cytosine, adenosine, and guanine (CAG) of more than 37 residues in the HD gene (currently referred to as HTT). Genetic evidence suggests that the CAG repeat expansion results in a gain of huntingtin function. While huntingtin and its numerous interactors have been implicated in a variety of essential cellular processes, the role of the full-length, endogenous protein remains unclear. Multiple studies have implicated huntingtin in processes related to cytoskeletal structure and dynamics in HD patients and model organisms. However, alterations in cellular dynamics related to the cytoskeleton—including cell adhesion—have not been characterized in a comprehensive, rigorous manner. Using Mus musculus genetic models of the HD mutation and/or deficiency and a Dictyostelium discoideum genetic deficiency model, I have undertaken an investigation of evolutionarily conserved huntingtin function in the cytoskeleton and cell adhesion. The results of these studies support a role for huntingtin in cell-cell and cell-substrate adhesion, as well as maintaining actin cytoskeletal structure. Furthermore, my thesis research sets the stage for future work to elucidate the molecular mechanism by which huntingtin is acting and determine the effect of the CAG repeat expansion on huntingtin function. Evolutionary conservation affords an invaluable tool to identify crucial function(s) of the huntingtin molecule and the effect of the pathogenic HD mutation on function, enabling therapeutic development while providing novel insights into cytoskeletal biology and cell adhesion.

Indexing (document details)
Advisor: MacDonald, Marcy E.
Commitee: Ahmad, Kami, Cowan, Chad C., McClatchey, Andrea I.
School: Harvard University
Department: Biology: Medical Sciences, Division of
School Location: United States -- Massachusetts
Source: DAI-B 74/06(E), Dissertation Abstracts International
Subjects: Genetics, Cellular biology, Microbiology
Keywords: Cell adhesion, Cytoskeleton, Dictyostelium, Huntingtin, Huntington's disease
Publication Number: 3553491
ISBN: 978-1-267-92971-6
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