title: Normalization of Overexpressed α-Synuclein Causing Parkinson's Disease By a Moderate Gene Silencing With RNA Interference.
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.
authors.affiliation: 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.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukuoka
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Fujikake
authors.affiliation: National Center Hospital, NCNP, Tokyo, Japan.
authors.forename: Shoko
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: National Center Hospital, NCNP, Tokyo, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Murata
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.affiliation: Department of Degenerative Neurological Disease, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Department of Molecular Pharmacology, National Institute of Neuroscience, NCNP, Tokyo, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hohjoh