title: Network Analysis Implicates Alpha-Synuclein (Snca) in the Regulation of Ovariectomy-Induced Bone Loss.
abstract: The postmenopausal period in women is associated with decreased circulating estrogen levels, which accelerate bone loss and increase the risk of fracture. Here, we gained novel insight into the molecular mechanisms mediating bone loss in ovariectomized (OVX) mice, a model of human menopause, using co-expression network analysis. Specifically, we generated a co-expression network consisting of 53 gene modules using expression profiles from intact and OVX mice from a panel of inbred strains. The expression of four modules was altered by OVX, including module 23 whose expression was decreased by OVX across all strains. Module 23 was enriched for genes involved in the response to oxidative stress, a process known to be involved in OVX-induced bone loss. Additionally, module 23 homologs were co-expressed in human bone marrow. Alpha synuclein (Snca) was one of the most highly connected "hub" genes in module 23. We characterized mice deficient in Snca and observed a 40% reduction in OVX-induced bone loss. Furthermore, protection was associated with the altered expression of specific network modules, including module 23. In summary, the results of this study suggest that Snca regulates bone network homeostasis and ovariectomy-induced bone loss.
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Gina
authors.initials: G
authors.lastname: Calabrese
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Larry D
authors.initials: LD
authors.lastname: Mesner
authors.affiliation: Department of Microbiology and Immunology, Georgetown University, Washington, DC 20007, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Foley
authors.affiliation: Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.|Departments of Public Health Science and Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Farber
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001842:Bone and Bones / Q000473:pathology; D004967:Estrogens / Q000172:deficiency; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015663:Osteoporosis, Postmenopausal / Q000378:metabolism*; D058866:Osteoporotic Fractures / Q000378:metabolism*; D010052:Ovariectomy; D018384:Oxidative Stress; D017698:Postmenopause; D055114:X-Ray Microtomography; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D004967:Estrogens; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein