The role of progranulin in the brain
department or school: Medicine, Faculty of
department or school: Medical Genetics, Department of
data provider: DSpace
degree campus: UBCV
creator: Petkau, Terri Lynn
issued: 2014-01-02T16:26:17Z
issued: 2013
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Frontotemporal lobar degeneration (FTLD) is a devastating, late-onset neurodegenerative disorder that causes profound behavioral abnormalities, language impairment, and alterations in personality in affected patients. As many as 40% of cases have a family history, and of these approximately 25% are due to loss-of-function mutations in the progranulin (GRN) gene. Progranulin-mediated FTLD, inherited in an autosomal dominant manner, is caused by haploinsufficiency. The purpose of this thesis was to characterize a novel mouse model of progranulin deficiency in order to study the role of progranulin in the brain and to understand how progranulin deficiency leads to neurodegeneration. The expression pattern of progranulin in the murine brain was examined using a lacZ reporter transgenic mouse line and immunohistochemistry. Progranulin is expressed at varying levels in all regions of the brain examined. Expression is strongest in the thalamus and hippocampus, moderate in the cortex, and low in the striatum and cerebellum. Double immunofluorescent labeling identified progranulin expression in mature neurons and microglia, the resident immune cells of the brain. Subsequently, a mouse model of progranulin deficiency was generated and characterized for abnormalities in behavior and neuropathology. The tests and outcome measures used were designed to reflect the behavioral and neuropathological changes observed in FTLD patients carrying GRN mutations. Heterozygous loss of progranulin produced no measurable alterations in behavior or pathology. Homozygous loss of progranulin in mice caused subtle behavioral abnormalities, intense microgliosis and astrogliosis throughout the brain, and exaggerated deposition of the aging pigment lipofuscin. Strain-dependent differences in the penetrance and expressivity of these phenotypes was observed, indicating that progranulin-dependent neurodegenerative phenotypes are modified by genetic background. In conclusion, progranulin-deficient mice…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/45678
note: THE ROLE OF PROGRANULIN IN THE BRAIN by Terri Lynn Petkau B.Sc., The University of Calgary, 2003 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in The Faculty of Graduate and Postdoctoral Studies (Genetics) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) December 2013 ? Terri Lynn Petkau, 2013 ii Abstract Frontotemporal lobar degeneration (FTLD) is a devastating, late-onset neurodegenerative disorder that causes profound behavioral abnormalities, language impairment, and alterations in personality in affected patients. As many as 40% of cases have a family history, and of these approximately 25% are due to loss-of-function mutations in the progranulin (GRN) gene. Progranulin-mediated FTLD, inherited in an autosomal dominant manner, is caused by haploinsufficiency. The purpose of this thesis was to characterize a novel mouse model of progranulin deficiency in order to study the role of progranulin in the brain and to understand how progranulin deficiency leads to neurodegeneration. The expression pattern of progranulin in the murine brain was examined using a lacZ reporter transgenic mouse line and immunohistochemistry. Progranulin is expressed at varying levels in all regions of the brain examined. Expression is strongest in the thalamus and hippocampus, moderate in the cortex, and low in the striatum and cerebellum. Double immunofluorescent labeling identified progranulin expression in mature neurons and microglia, the resident immune cells of the brain. Subsequently, a mouse model of progranulin deficiency was generated and characterized for abnormalities in behavior and neuropathology. The tests and outcome iii measures used were designed to reflect the behavioral and neuropathological changes observed in FTLD patients carrying GRN mutations. Heterozygous loss of progranulin produced no measurable alterations in behavior or pathology. Homozygous loss of progranulin in mice caused subtle behavioral abnormalities…
has type: Thesis/Dissertation
date issued: 2014-05
is shown at: 10.14288/1.0165721
language: eng
degree discipline: Genetics
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
type: Text
identifier URI: http://hdl.handle.net/2429/45678