The Anticholinesterase Phenserine and Its Enantiomer Posiphen as 5′Untranslated-Region-Directed Translation Blockers of the Parkinson’s Alpha Synuclein Expression
Figure 1
The 5′untranslated region (5′UTR) of the Parkinson’s disease alpha-synuclein (SNCA) transcript is homologous to the iron-responsive element (IRE) in H-ferritin mRNA. (a) Top panel: The SNCA 5′UTR is encoded by exon-1 and exon-2 of the SNCA gene, which can be alternatively spliced to generate either a shorter exon-1/-2 transcript or a longer exon-1′-2 transcript [58]. Bottom panel: evolutionary alignment of the SNCA 5′UTR relative to the human sequence and the CAGUGN loop/splice site sequences [33]. We quantified the homology across the SNCA splice junction in the 5′untranslated region. (b) RNA/FOLD computer program predictions of RNA stem loops from SNCA 5′UTR sequences ( kcal/mol). The human SNCA stem loop resembles the classical IRE RNA stem loop (5′CAGUGN3’ loop motif) that controls iron-dependent L- and H-ferritin translation and transferrin receptor (TfR) mRNA stability. Stem loops from the 5′UTRs of several species were predicted to be folded, as described in the Materials and Methods section, and the pseudotriloop AGU is depicted in red lettering at the apex of the H-ferritin IRE [59] where the analogous AGA from the APP IRE is depicted [50]. The human SNCA mRNA exhibited an AGU triloop, whereas, in lower vertebrates, this AGU motif was located in the stem regions of these transcripts. Shown are the arrangement of splice sites and 5′UTR structures in the SNCA, SNCB, SNCG mRNAs. Tabulated: the first table shows the homology between the IRE-like domains in each exon of the human alpha-synuclein compared to its counterparts in different mammalian species. The second table shows the homology between the 5′untranslated regions of SNCA with the APP and ferritin L- and H-chains. This data underscored our identification of cotranslational repression of APP and alpha-synuclein by small molecules, such as phenserine and posiphen.
