title: Cellular and molecular characterization of oxidative stress in olfactory epithelium of Harlequin mutant mouse.
abstract: Oxidative stress in the olfactory system is a major factor associated with age-related olfactory impairment, although the mechanisms by which this occurs are not completely understood. The Harlequin mutant mouse (Hq/Y), which carries an X-linked recessive mutation in the Aifm1 gene, is a model of progressive oxidative stress-induced neurodegeneration in the cerebellum and retina. To determine whether the Hq/Y mutant mouse is a suitable model of oxidative stress-associated olfactory aging, we investigated cellular and molecular changes in the olfactory epithelium (OE) and olfactory bulb (OB) of 6-month-old male Hq/Y mice compared to those in sex-matched littermate controls (+/Y) and in age- and sex-matched C57BL/6 mice. Immunoreactivity for apoptosis-inducing factor, the protein product of Aifm1, was localized in mature olfactory sensory neurons (mOSNs) in +/Y mice but was rarely detected in Hq/Y mice. Hq/Y mice also exhibited increased lipofuscin autofluorescence and increased immunoreactivity for an oxidative DNA/RNA damage marker in mOSNs and in mitral/tufted cells in the OB and an increased number of cleaved caspase-3 immunoreactive apoptotic cells in the OE. Microarray analysis demonstrated that Aifm1 expression was down-regulated by 80% in the OE of Hq/Y mice compared to that in +/Y mice. Most significantly, regulated genes were classified into functional categories of cell signaling/apoptosis/cell cycle, oxidative stress/aging, and cytoskeleton/extracellular matrix/transport-associated. Analysis with EASE software indicated that the functional categories significantly overrepresented in Hq/Y mice included up-regulated mitochondrial genes and down-regulated cytoskeletal organization- and neurogenesis-related genes. Our results strongly support the Hq/Y mutant mouse being a novel model for mechanistic studies of oxidative stress-associated olfactory aging.
authors.affiliation: Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
authors.forename: Radhika A
authors.initials: RA
authors.lastname: Vaishnav
authors.forename: Marilyn L
authors.initials: ML
authors.lastname: Getchell
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hersh
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Stromberg
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Getchell
mesh_terms: D000367:Age Factors; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D019295:Computational Biology / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046228:Microarray Analysis / Q000379:methods; D008840:Microfilament Proteins; D009475:Neurons, Afferent / Q000378:metabolism*; D009831:Olfactory Mucosa / Q000166:cytology* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D012737:Sex Factors
chemical_list: C491049:Aif1 protein, mouse; D051033:Apoptosis Inducing Factor; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins