Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153.
Genetic and biochemical studies have established a central role for alpha-synuclein accumulation in the pathogenesis of Parkinson disease. Here, two microRNAs, namely mir-7 and mir-153, have been identified to regulate alpha-synuclein levels post-transcriptionally. These microRNAs bind specifically to the 3'-untranslated region of alpha-synuclein and down-regulate its mRNA and protein levels, with their effect being additive. They are expressed predominantly in the brain with a pattern that mirrors synuclein expression in different tissues as well as during neuronal development, indicating that they play a tuning role in the amount of alpha-synuclein produced. Overexpression of mir-7 and mir-153 significantly reduces endogenous alpha-synuclein levels, whereas inhibition of mir-7 and mir-153 enhances translation of a luciferase construct bearing the alpha-synuclein 3'-untranslated region in primary neurons. These findings reveal a significant additional mechanism by which alpha-synuclein is regulated and point toward new therapeutic regimes for lowering endogenous alpha-synuclein levels in patients with familial or sporadic Parkinson disease.
Doxakis
Epaminondas
E
Basic Neurosciences Division, Biomedical Research Foundation of the Academy of Athens, Soranou Efesiou 4, Athens 11527, Greece. edoxakis@bioacademy.gr
D020413:3' Untranslated Regions; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D014176:Protein Biosynthesis; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
D020413:3' Untranslated Regions; D035683:MicroRNAs; D051844:alpha-Synuclein