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Mutant huntingtin reduces palmitoylation of GAD65 and impairs its vesicular trafficking

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Date Issued:
2012
Summary:
Huntington's disease (HD) is caused by an expanded plyglutamine repeat in the huntingtin protein. In this study, I focused on the effect of the mutant huntingtin protein (mhtt) on the subcellular localization of glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing gama-aminobutyric acid (GABA). Subcellular distribution of GAD65 is significantly altered in two neuronal cell lines that express either the N-terminus or full length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal huntingtin (Htt). However, it diffuses in the cytosol of cells expressing mhtt. Palmitoylation of GAD65 is required for GAD65 trafficking, and I demonstrated the palmitoylation of GAD65 is reduced in the HD model. Overexpression of huntingtin-interacting protein 14 (HIP14), the enzyme that palmitoylates GAD65, rescues GAD65 palmitoylation and vesicle-associated trafficking. This data suggests that impairment of GAD65 palmitoylation by mhtt may alter its localization and lead to altered inhibitory neurotransmission in HD.
Title: Mutant huntingtin reduces palmitoylation of GAD65 and impairs its vesicular trafficking.
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Name(s): Rush, Daniel.
Charles E. Schmidt College of Medicine
Department of Biomedical Science
Type of Resource: text
Genre: Electronic Thesis Or Dissertation
Date Issued: 2012
Publisher: Florida Atlantic University
Physical Form: electronic
Extent: x, 39 p. : ill. (some col.)
Language(s): English
Summary: Huntington's disease (HD) is caused by an expanded plyglutamine repeat in the huntingtin protein. In this study, I focused on the effect of the mutant huntingtin protein (mhtt) on the subcellular localization of glutamic acid decarboxylase (GAD), the enzyme responsible for synthesizing gama-aminobutyric acid (GABA). Subcellular distribution of GAD65 is significantly altered in two neuronal cell lines that express either the N-terminus or full length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal huntingtin (Htt). However, it diffuses in the cytosol of cells expressing mhtt. Palmitoylation of GAD65 is required for GAD65 trafficking, and I demonstrated the palmitoylation of GAD65 is reduced in the HD model. Overexpression of huntingtin-interacting protein 14 (HIP14), the enzyme that palmitoylates GAD65, rescues GAD65 palmitoylation and vesicle-associated trafficking. This data suggests that impairment of GAD65 palmitoylation by mhtt may alter its localization and lead to altered inhibitory neurotransmission in HD.
Identifier: 810329765 (oclc), 3352831 (digitool), FADT3352831 (IID), fau:3909 (fedora)
Note(s): by Daniel Rush.
Thesis (M.S.)--Florida Atlantic University, 2012.
Includes bibliography.
Electronic reproduction. Boca Raton, Fla., 2012. Mode of access: World Wide Web.
Subject(s): Glutamic acids -- Antagonists
Cellular signal transduction
Proteolytic enzymes -- Research
Proteins -- Physiological transport
Huntington's chorea -- Research
Persistent Link to This Record: http://purl.flvc.org/FAU/3352831
Use and Reproduction: http://rightsstatements.org/vocab/InC/1.0/
Host Institution: FAU