p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity.
p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity.
复制标题
DOI：
10.1016/j.neuro.2016.04.012
复制
发表时间：
2017-03
期刊：
影响因子：
3.4
通讯作者：
Kanthasamy, Anumantha G.
中科院分区：
文献类型：
--
作者：
Kim, Dong-Suk;Jin, Huajun;Anantharam, Vellareddy;Gordon, Richard;Kanthasamy, Arthi;Kanthasamy, Anumantha G.
长期暴露于高水平的锰（Mn）与帕金森样运动障碍有关，由基底神经节内的锥体外系运动系统功能障碍引起。然而，锰诱导的神经毒性的确切细胞和分子机制仍然难以捉摸。在这项研究中，我们用30 mg/kg Mn经口灌胃治疗C57/BL 6 J小鼠30天。有趣的是，在锰暴露小鼠的黑质组织中，我们发现N端截短的p73蛋白亚型（Δ Np 73）显著下调。为了进一步确定锰诱导的p73下调锰神经毒性的功能作用，我们研究了锰对p73基因表达和N27多巴胺能神经元模型中细胞凋亡的影响之间的相互关系。与我们的动物研究一致，300 μM Mn处理显著抑制N27多巴胺能细胞中p73 mRNA的表达。我们进一步确定，在Mn处理的N27细胞和原代纹状体培养物中，Δ Np 73同种型的蛋白水平也降低。此外，Δ Np 73的过表达对Mn诱导的神经毒性具有适度的细胞保护作用。两者合计，我们的研究结果表明，锰暴露下调p73基因的表达，从而增强对凋亡性细胞死亡的敏感性。因此，进一步表征p73基因下调的细胞机制将提高我们对锰神经毒性的分子基础的理解。
Chronic exposure to elevated levels of manganese (Mn) has been linked to a Parkinsonian-like movement disorder, resulting from dysfunction of the extrapyramidal motor system within the basal ganglia. However, the exact cellular and molecular mechanisms of Mn-induced neurotoxicity remain elusive. In this study, we treated C57/BL6J mice with 30 mg/kg Mn via oral gavage for 30 days. Interestingly, in nigral tissues of Mn-exposed mice, we found a significant downregulation of the truncated isoform of p73 protein at the N-terminus (ΔNp73). To further determine the functional role of Mn-induced p73 downregulation in Mn neurotoxicity, we examined the interrelationship between the effect of Mn on p73 gene expression and apoptotic cell death in an N27 dopaminergic neuronal model. Consistent with our animal study, a 300 μM Mn treatment significantly suppressed p73 mRNA expression in N27 dopaminergic cells. We further determined that protein levels of the ΔNp73 isoform was also reduced in Mn-treated N27 cells and primary striatal cultures. Furthermore, overexpression of ΔNp73 conferred modest cellular protection against Mn-induced neurotoxicity. Taken together, our results demonstrate that Mn exposure downregulates p73 gene expression resulting in enhanced susceptibility to apoptotic cell death. Thus, further characterization of the cellular mechanism underlying p73 gene downregulation will improve our understanding of the molecular underpinnings of Mn neurotoxicity.
登录
查看更多内容
DOI：
10.1196/annals.1332.017
发表时间：
2004-01-01
期刊：
PROTECTIVE STRATEGIES FOR NEURODEGENERATIVE DISEASES
影响因子：
--
作者：
Anantharam, V;Kitazawa, M;Kanthasamy, AG
通讯作者：
Kanthasamy, AG
影响因子：
4.8
作者：
Jin, Huajun;Kanthasamy, Arthi;Kanthasamy, Anumantha G.
通讯作者：
Kanthasamy, Anumantha G.
影响因子：
4.2
作者：
Gonzalez, Laura E.;Juknat, A. Ana;Kotler, Monica L.
通讯作者：
Kotler, Monica L.
影响因子：
10.5
作者：
Asher, G;Tsvetkov, P;Shaul, Y
通讯作者：
Shaul, Y
DOI：
10.1016/j.jtemb.2011.08.144
发表时间：
2011-12
期刊：
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
影响因子：
--
作者：
Bowman AB;Kwakye GF;Herrero Hernández E;Aschner M
通讯作者：
Aschner M