Transcriptome analysis of a rotenone model of parkinsonism reveals complex I-tied and -untied toxicity mechanisms common to neurodegenerative diseases.
Transcriptome analysis of a rotenone model of parkinsonism reveals complex I-tied and -untied toxicity mechanisms common to neurodegenerative diseases.
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DOI：
10.1371/journal.pone.0044700
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Schiestl RH
中科院分区：
文献类型：
--
作者：
Cabeza-Arvelaiz Y;Schiestl RH
杀虫剂鱼藤酮是一种神经毒素，它抑制线粒体复合物I并使微管（MT）不稳定，已与帕金森病（PD）病因学相关，并经常用于模拟这种神经退行性疾病（ND）。鱼藤酮的许多作用机制是神经变性的假定机制;然而，它们尚未完全理解。因此，研究鱼藤酮影响的功能通路有助于了解神经营养不良的发病机制。本报告描述了神经母细胞瘤（NB）细胞系长期暴露于轻度毒性和中度毒性剂量的鱼藤酮的转录组分析。结果揭示了鱼藤酮的复杂多效性反应，影响各种细胞事件，包括细胞周期，DNA损伤反应，增殖，分化，衰老和细胞死亡，这可能导致生存或神经变性，这取决于暴露的剂量和时间以及细胞表型。该反应包括一系列生理途径，由转录和表观遗传调控网络调节，可能由稳态改变激活。建议将MT不稳定的贡献鱼藤酮毒性的途径来解释复杂的I-独立的鱼藤酮诱导的代谢和氧化还原稳态的改变。推测的机制涉及微管蛋白对线粒体电压依赖性阴离子通道（VDACs）的阻断，其与鱼藤酮诱导的其他细胞器功能障碍相结合，可能是与各种ND（包括PD、AD及其变体形式）的病理生理学方面相关的许多推测的神经变性机制的基础。因此，对这些途径的进一步研究可能有助于确定这些ND的新治疗途径。
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.
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影响因子：
64.5
作者：
Bassermann, Florian;Frescas, David;Guardavaccaro, Daniele;Busino, Luca;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
4.3
作者：
Chen, Yumay;Chen, Chi-Fen;Chen, Phang-Lang
通讯作者：
Chen, Phang-Lang
影响因子：
4.1
作者：
Basu SS;Blair IA
通讯作者：
Blair IA
DOI：
10.1073/pnas.1014263108
发表时间：
2011-03-29
影响因子：
11.1
作者：
Chagraoui, Jalila;Hebert, Josee;Sauvageau, Guy
通讯作者：
Sauvageau, Guy
影响因子：
15.1
作者：
Cabeza-Arvelaiz Y;Fleming SM;Richter F;Masliah E;Chesselet MF;Schiestl RH
通讯作者：
Schiestl RH