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Global gene profiling of rotenone-induced neuronal death

ABSTRACT: Rotenone is a naturally occurring toxic substance from the Leguminosa plant and belongs to the group of compounds known as rotenoids (Bové et al., 2005). It is commercially used as a pesticide and is epidemiologically linked to PD. Being lipophilic, rotenone can diffuse across biological membranes in the body and gain entry to all the organs and cells (Bové et al., 2005). Rotenone can bind to complex I of the electron transport chain (ETC) and inhibit the enzymatic activity of the NADH-ubiquinone reductase (Schuler and Casida, 2001). This interferes with the oxidation phosphorylation process, and eventually causes cell damage via oxidative stress. Rotenone may also cause the depolymerisation of microtubules into tubulin monomers (Marshall and Himes, 1978). Accumulation of tubulin monomers is potentially cytotoxic, and it is believed that parkin reverses cytotoxicity by ubiquitinating these monomers and targeting them for proteasome degradation (Ren et al., 2003.). Unfortunately, in PD patients with parkin mutations, this is not possible and tubulin accumulates to harmful levels in the cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE22997 | GEO | 2013/12/31

SECONDARY ACCESSION(S): PRJNA127837

REPOSITORIES: GEO

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Project description:The pesticide rotenone, a neurotoxin that inhibits the mitochondrial complex I, and destabilizes microtubules (MT) has been linked to Parkinson disease (PD) etiology and is often used to model this neurodegenerative disease (ND). Many of the mechanisms of action of rotenone are posited mechanisms of neurodegeneration; however, they are not fully understood. Therefore, the study of rotenone-affected functional pathways is pertinent to the understanding of NDs pathogenesis. This report describes the transcriptome analysis of a neuroblastoma (NB) cell line chronically exposed to marginally toxic and moderately toxic doses of rotenone. The results revealed a complex pleiotropic response to rotenone that impacts a variety of cellular events, including cell cycle, DNA damage response, proliferation, differentiation, senescence and cell death, which could lead to survival or neurodegeneration depending on the dose and time of exposure and cell phenotype. The response encompasses an array of physiological pathways, modulated by transcriptional and epigenetic regulatory networks, likely activated by homeostatic alterations. Pathways that incorporate the contribution of MT destabilization to rotenone toxicity are suggested to explain complex I-independent rotenone-induced alterations of metabolism and redox homeostasis. The postulated mechanisms involve the blockage of mitochondrial voltage-dependent anions channels (VDACs) by tubulin, which coupled with other rotenone-induced organelle dysfunctions may underlie many presumed neurodegeneration mechanisms associated with pathophysiological aspects of various NDs including PD, AD and their variant forms. Thus, further investigation of such pathways may help identify novel therapeutic paths for these NDs. SK-N-MC cells were grown in three different conditions: media + vehicle (EtOH), media + a sublethal dose (5 nM) of rotenone, and media + a slightly toxic dose (50 nM) of rotenone. Gene expression was examined at 1 and 4 weeks of rotenone treatment. Three experiments were performed, each lasting 1 and 4 weeks. For each experiment, 5 separate dishes of vehicle-treated, and rotenone-treated cells were harvested at 1 and 4 weeks (30 independent samples at each time point) and pooled into 3 samples (vehicle treated,and rotenone treated with 5 nM and 50 nM) at each time point for a total of 18 individual samples from all thre experiments. Total RNA isolated from each of the 18 individual samples was used to prepared labeled cRNA and hybridized to one Genechip (Affymetrix) Human Genome array HG-U133A at the UCLA microarray core facility (http://microarray.genetics.ucla.edu/). After QC check, the data was normalized and used to assess expression indexes and fold changes (FC > 2.0, compared to vehicle-treated controls) using the model-based expression indexes (MBEI) method implemented in dCHIP, ( http://biosun1.harvard.edu/complab/dchip/), and the Signifiance Analysis of Microarrays (SAM) software for multiple test corrections. Enrichment analysis was performed by the functional annotation tools implemented in DAVID ( http://david.abcc.ncifcrf.gov), to ascertain sets of rotenone DRGs that are enriched in certain biological annotations.

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Global gene profiling of rotenone-induced neuronal death

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