Dissertation/Thesis Abstract

Characterizing the Effects of Mutant Huntingtin and IKK Beta on IL-34 Expression
by Sabbaugh, Adam, M.S., California State University, Los Angeles, 2017, 62; 10270139
Abstract (Summary)

A major determinant of Huntington’s disease (HD) pathology is the expansion of a polyglutamine (polyQ) repeat in the exon-1 of Huntingtin protein (HTT). Proteolytic processing of mutant HTT liberates exon-1 (mHDx1) monomers, which oligomerize and disrupt cellular homeostasis. mHDx1 oligomers interact with various signaling proteins including the IkappaB kinase (IKK)/nuclear factor-kappaB (NF-κB) complex, a prominent regulator of inflammation. Neuroinflammation is implicated in the onset and progression of HD. A hallmark of neuroinflammation is the expansion of activated microglia in the central nervous system (CNS). Microglia communicate with neurons by several receptor-ligand systems. One is interleukin-34 (IL-34), a cytokine which plays a prominent role in microglial development and function. In the CNS, neurons produce and secrete IL-34, which binds to colony stimulating factor 1-receptor (CSF1-R) expressed by microglia. Factors that regulate neuroinflammation in Huntington’s disease remain unknown. For my thesis project, I participated in various experiments to determine whether mHDx1 influences IL-34 production in neurons. The accumulated data suggest that mHDx1 induces IL-34 expression in dopaminergic neurons derived from human embryonic stem cells. IL-34 production is also induced by stressful stimuli known to activate IKKβ. IKKβ-dependent aggregation of mHDx1 is critical for the production of IL-34. Secreted IL-34 has no visible effect on the aggregation of mHDx1 in neurons suggesting that it may influence other CNS cells such as microglia. Overall, my efforts helped to identify IL-34 production as a downstream effect of mHDx1 aggregation in neurons and will facilitate further studies on neuron-microglia communications in Huntington’s disease.

Indexing (document details)
Advisor: Khoshnan, Ali
Commitee: Nissen, Robert, Sharp, Sandra
School: California State University, Los Angeles
Department: Biological Sciences
School Location: United States -- California
Source: MAI 56/04M(E), Masters Abstracts International
Subjects: Biology
Keywords: Huntington's disease
Publication Number: 10270139
ISBN: 978-1-369-84762-8
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