Febbraro Fabia, Giorgi Marcello, Caldarola Sara, Loreni Fabrizio, Romero-Ramos Marina
CNS Disease Modeling Group, Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
Neuroreport. 2012 Jun 20;23(9):576-80. doi: 10.1097/WNR.0b013e328354a1f0.
Several studies have suggested an interaction between α-synuclein protein and iron in Parkinson's disease. The presence of iron together with α-synuclein in Lewy bodies, the increase of iron in the substantia nigra and the correlation between polymorphism of the several genes implicated in iron metabolism and Parkinson's disease, support a role for iron in the neurodegeneration. Analysis of post mortem brains revealed increased amount of insoluble α-synuclein protein despite unchanged/reduced levels of α-synuclein mRNA in Parkinson's disease. Interestingly, on the basis of the presence of a putative iron responsive element in the 5'-UTR, it has been suggested that there is a possible iron-dependent translational control of human α-synuclein mRNA. Considering the similarity between the sequences present in human α-synuclein mRNA and the ferritin iron responsive element, we postulated that iron deficiency would decrease the translation of α-synuclein mRNA. Here we used HEK293 cells treated with iron chelator deferoxamine or ferric ammonium citrate to verify the possible iron-dependent translational control of human α-synuclein biosynthesis. We show that the amount of polysome-associated endogenous human α-synuclein mRNA decreases in presence of deferoxamine. Our data demonstrate that human α-synuclein expression is regulated by iron mainly at the translational level. This result not only supports a role for iron in the translational control of α-synuclein expression, but also suggests that iron chelation may be a valid approach to control α-synuclein levels in the brain.
多项研究表明，在帕金森病中α-突触核蛋白与铁之间存在相互作用。路易小体中铁与α-突触核蛋白共存、黑质中铁含量增加以及参与铁代谢的多个基因的多态性与帕金森病之间的相关性，均支持铁在神经退行性变中发挥作用。对死后大脑的分析显示，在帕金森病中，尽管α-突触核蛋白mRNA水平未变或降低，但不溶性α-突触核蛋白的含量却增加了。有趣的是，基于5'-非翻译区中存在假定的铁反应元件，有人提出人类α-突触核蛋白mRNA可能存在铁依赖性翻译调控。考虑到人类α-突触核蛋白mRNA中存在的序列与铁蛋白铁反应元件之间的相似性，我们推测缺铁会降低α-突触核蛋白mRNA的翻译。在此，我们使用用铁螯合剂去铁胺或柠檬酸铁铵处理的HEK293细胞，以验证人类α-突触核蛋白生物合成可能存在的铁依赖性翻译调控。我们发现，在去铁胺存在的情况下，多核糖体相关的内源性人类α-突触核蛋白mRNA的量会减少。我们的数据表明，人类α-突触核蛋白的表达主要在翻译水平受铁的调控。这一结果不仅支持铁在α-突触核蛋白表达的翻译调控中发挥作用，还表明铁螯合可能是控制大脑中α-突触核蛋白水平的有效方法。
