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Takahashi M, Suzuki M, Fukuoka M, et al. Normalization of Overexpressed α-Synuclein Causing Parkinson's Disease By a Moderate Gene Silencing With RNA Interference. Mol Ther Nucleic Acids. 2015;4:e241doi: 10.1038/mtna.2015.14.
Takahashi, M., Suzuki, M., Fukuoka, M., Fujikake, N., Watanabe, S., Murata, M., Wada, K., Nagai, Y., & Hohjoh, H. (2015). Normalization of Overexpressed α-Synuclein Causing Parkinson's Disease By a Moderate Gene Silencing With RNA Interference. Molecular therapy. Nucleic acids, 4e241. https://doi.org/10.1038/mtna.2015.14
Takahashi, Masaki, et al. "Normalization of Overexpressed α-Synuclein Causing Parkinson's Disease By a Moderate Gene Silencing With RNA Interference." Molecular therapy. Nucleic acids vol. 4 (2015): e241. doi: https://doi.org/10.1038/mtna.2015.14
Takahashi M, Suzuki M, Fukuoka M, Fujikake N, Watanabe S, Murata M, Wada K, Nagai Y, Hohjoh H. Normalization of Overexpressed α-Synuclein Causing Parkinson's Disease By a Moderate Gene Silencing With RNA Interference. Mol Ther Nucleic Acids. 2015 May 12;4:e241. doi: 10.1038/mtna.2015.14. PMID: 25965551.
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Mol Ther Nucleic Acids. 2015 May 12;4:e241. doi: 10.1038/mtna.2015.14.

Normalization of Overexpressed α-Synuclein Causing Parkinson's Disease By a Moderate Gene Silencing With RNA Interference.

Molecular therapy. Nucleic acids

Masaki Takahashi, Mari Suzuki, Masashi Fukuoka, Nobuhiro Fujikake, Shoko Watanabe, Miho Murata, Keiji Wada, Yoshitaka Nagai, Hirohiko Hohjoh

Affiliations

  1. 1] Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo, Japan [2] Present address: Division of RNA Medical Science, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  2. Department of Degenerative Neurological Disease, National Institute of Neuroscience, NCNP, Tokyo, Japan.
  3. Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
  4. National Center Hospital, NCNP, Tokyo, Japan.

PMID: 25965551 DOI: 10.1038/mtna.2015.14

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.

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