title: Gene expression profiling of rotenone-mediated cortical neuronal death: evidence for inhibition of ubiquitin-proteasome system and autophagy-lysosomal pathway, and dysfunction of mitochondrial and calcium signaling.
abstract: Mitochondrial dysfunction and oxidative stress are currently considered two key mechanisms contributing to pathobiology in neurodegenerative conditions. The current study investigated the temporal molecular events contributing to programmed cell death after treatment with the mitochondrial complex I inhibitor rotenone. Microarray analysis was performed using cultured neocortical neurons treated with 10nM rotenone for 8, 15, and 24h. Genes showing at least ±1.2-fold change in expression at one time point were considered significant. Transcriptomic analysis of the 4178 genes probes revealed major changes to nine biological processes, including those eliciting mitochondrial dysfunction, activation of calcium signaling, increased expression of apoptotic genes, and downplay of chaperones/co-chaperones, ubiquitin-proteasome system and autophagy. These data define targets for intervention where mitochondrial complex I dysfunction plays a substantial role, most notably Parkinson's disease.
authors.affiliation: Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Yann Wan
authors.initials: YW
authors.lastname: Yap
authors.forename: Minghui Jessica
authors.initials: MJ
authors.lastname: Chen
authors.forename: Zhao Feng
authors.initials: ZF
authors.lastname: Peng
authors.forename: Jayapal
authors.initials: J
authors.lastname: Manikandan
authors.forename: Jian Ming Jeremy
authors.initials: JM
authors.lastname: Ng
authors.forename: Roxana M
authors.initials: RM
authors.lastname: Llanos
authors.forename: Sharon
authors.initials: S
authors.lastname: La Fontaine
authors.forename: Philip M
authors.initials: PM
authors.lastname: Beart
authors.forename: Nam Sang
authors.initials: NS
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020869:Gene Expression Profiling; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012402:Rotenone / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D012402:Rotenone; D046988:Proteasome Endopeptidase Complex