title: Temporal gene expression patterns in G93A/SOD1 mouse.
abstract: Amyotrophic lateral sclerosis (ALS) is a generally fatal degenerative disorder of motor neurons that has no known cure. Many pathological processes have been implicated. However, the early, initiating events in the disease are poorly understood. We performed multivariate analyses of gene expression of 21 selected genes from categories including glutamate neurotoxicity, oxidative stress, neuroinflammation, aberrant metal ion regulation, apoptosis, and abnormal microglial function on G93A SOD1 mice. These animals develop symptoms of motor neuron dysfunction at about 12 weeks of age, and die at age 18 to 20 weeks. We analyzed animals at both presymptomatic and symptomatic stages. Differential regulation of several genes involved in neuroinflammation, including TNF-alpha, IL- RA, CD86, CD200R and Groalpha, was observed in presymptomatic mice, aged 6-9 weeks, while expression of genes representative of other processes was not altered until the animals reached symptomatic stages. Analysis of expression of inflammatory genes and microglia related genes together also revealed a highly significant change in mutant mice relative to wildtype at 6-9 weeks. These changes were due to the presence of the mutant gene, and not simply to overexpression of a SOD1 gene. These findings are discussed in relation to possible roles of microglia function in the development of ALS.
authors.affiliation: The Forbes Norris ALS Research Center, California Pacific Medical Center Research Institute, San Francisco, CA 94115, USA.
authors.forename: Ling-Chun
authors.initials: LC
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Yong
authors.initials: Y
authors.lastname: Ben
authors.forename: Belma
authors.initials: B
authors.lastname: Zukic
authors.forename: Sheila
authors.initials: S
authors.lastname: Ignacio
authors.forename: Dan
authors.initials: D
authors.lastname: Moore
authors.forename: Nancy
authors.initials: N
authors.lastname: Lee
mesh_terms: D000367:Age Factors; D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D015999:Multivariate Analysis; D009474:Neurons / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000096:biosynthesis; D013116:Spinal Cord / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D027322:Amino Acid Transport System X-AG; D015703:Antigens, CD; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D050491:Glutamate Plasma Membrane Transport Proteins; D012333:RNA, Messenger; D027981:Symporters; D014409:Tumor Necrosis Factor-alpha; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase