normalization of overexpressed α-synuclein causing parkinson's disease by a moderate gene silencing with rna interference
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2015
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Abstract
The α-synuclein (SNCA) gene is a responsible gene for Parkinson's disease (PD); and not only nucleotide variations but also overexpression of SNCA appears to be involved in the pathogenesis of PD. A specific inhibition against mutant SNCA genes carrying nucleotide variations may be feasible by a specific silencing such as an allele-specific RNA interference (RNAi); however, there is no method for restoring the SNCA overexpression to a normal level. Here, we show that an atypical RNAi using small interfering RNAs (siRNAs) that confer a moderate level of gene silencing is capable of controlling overexpressed SNCA genes to return to a normal level; named “expression-control RNAi” (ExCont-RNAi). ExCont-RNAi exhibited little or no significant off-target effects in its treated PD patient's fibroblasts that carry SNCA triplication. To further assess the therapeutic effect of ExCont-RNAi, PD-model flies that carried the human SNCA gene underwent an ExCont-RNAi treatment. The treated PD-flies demonstrated a significant improvement in their motor function. Our current findings suggested that ExCont-RNAi might be capable of becoming a novel therapeutic procedure for PD with the SNCA overexpression, and that siRNAs conferring a moderate level of gene silencing to target genes, which have been abandoned as useless siRNAs so far, might be available for controlling abnormally expressed disease-causing genes without producing adverse effects.
| Reference Key |
takahashi2015molecularnormalization
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| Authors | ;Masaki Takahashi;Mari Suzuki;Masashi Fukuoka;Nobuhiro Fujikake;Shoko Watanabe;Miho Murata;Keiji Wada;Yoshitaka Nagai;Hirohiko Hohjoh |
| Journal | coordination chemistry reviews |
| Year | 2015 |
| DOI |
10.1038/mtna.2015.14
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| URL | |
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