The role of progranulin in the brain

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 develop neuropathological phenotypes that indicate increased neuronal stress and a decline in overall brain health that progresses with age. Although dramatic behavioral changes and overt neuronal loss similar to what is seen FTLD patients is not apparent in progranulin-deficient mice, the presence of robust, age-dependent neurodegenerative abnormalities makes progranulin knockout mice a useful model for certain aspects of progranulin-dependent FTLD.Medicine, Faculty ofMedical Genetics, Department ofGraduat