α-Synuclein expression is modulated at the translational level by iron.

Several studies have suggested an interaction between a-synuclein protein and iron in Parkinson’s disease. The presence of iron together with a-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 a-synuclein protein despite unchanged/reduced levels of a-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 a-synuclein mRNA. Considering the similarity between the sequences present in human a-synuclein mRNA and the ferritin iron responsive element, we postulated that iron deficiency would decrease the translation of a-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 a-synuclein biosynthesis. We show that the amount of polysome-associated endogenous human a-synuclein mRNA decreases in presence of deferoxamine. Our data demonstrate that human a-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 a-synuclein expression, but also suggests that iron chelation may be a valid approach to control a-synuclein levels in the brain.