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Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases
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...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436760/ https://www.ncbi.nlm.nih.gov/pubmed/22970289 http://dx.doi.org/10.1371/journal.pone.0044700 |
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author | Cabeza-Arvelaiz, Yofre Schiestl, Robert H. |
author_facet | Cabeza-Arvelaiz, Yofre Schiestl, Robert H. |
author_sort | Cabeza-Arvelaiz, Yofre |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-3436760 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-34367602012-09-11 Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases Cabeza-Arvelaiz, Yofre Schiestl, Robert H. PLoS One Research Article 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. Public Library of Science 2012-09-07 /pmc/articles/PMC3436760/ /pubmed/22970289 http://dx.doi.org/10.1371/journal.pone.0044700 Text en © 2012 Cabeza-Arvelaiz, Schiestl http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Cabeza-Arvelaiz, Yofre Schiestl, Robert H. Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases |
title | Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases |
title_full | Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases |
title_fullStr | Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases |
title_full_unstemmed | Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases |
title_short | Transcriptome Analysis of a Rotenone Model of Parkinsonism Reveals Complex I-Tied and -Untied Toxicity Mechanisms Common to Neurodegenerative Diseases |
title_sort | transcriptome analysis of a rotenone model of parkinsonism reveals complex i-tied and -untied toxicity mechanisms common to neurodegenerative diseases |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436760/ https://www.ncbi.nlm.nih.gov/pubmed/22970289 http://dx.doi.org/10.1371/journal.pone.0044700 |
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