title: α-Synuclein expression is modulated at the translational level by iron.
abstract: 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.
authors.affiliation: CNS Disease Modeling Group, Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors.forename: Fabia
authors.initials: F
authors.lastname: Febbraro
authors.forename: Marcello
authors.initials: M
authors.lastname: Giorgi
authors.forename: Sara
authors.initials: S
authors.lastname: Caldarola
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loreni
authors.forename: Marina
authors.initials: M
authors.lastname: Romero-Ramos
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007501:Iron / Q000502:physiology*; D007668:Kidney / Q000166:cytology; D016631:Lewy Bodies / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012377:Rodentia; D017262:Siderophores / Q000494:pharmacology; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*
chemical_list: D005290:Ferric Compounds; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; C497604:SNCA protein, human; D017262:Siderophores; D051844:alpha-Synuclein; D007501:Iron; D003676:Deferoxamine; C013531:ferric ammonium citrate