Transgenic Small Interfering RNA Halts Amyotrophic Lateral Sclerosis in a Mouse Model

Many autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with copper/zinc superoxide dismutase (SOD1) mutation may be induced by missense point mutations that result in the production of proteins with toxic properties. Reduction in the encoding of proteins from such muta...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2005-12, Vol.280 (52), p.42826-42830
Main Authors: Saito, Yuki, Yokota, Takanori, Mitani, Tasuku, Ito, Kaoru, Anzai, Masayuki, Miyagishi, Makoto, Taira, Kazunari, Mizusawa, Hidehiro
Format: Article
Language:English
Subjects:
Amyotrophic Lateral Sclerosis - therapy
Animals
Base Sequence
Blotting, Northern
Blotting, Western
Disease Models, Animal
Disease Progression
Female
Gene Silencing
Genetic Vectors
Genome
Humans
Immunohistochemistry
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Molecular Sequence Data
Mutation
Mutation, Missense
Phenotype
Plasmids - metabolism
Point Mutation
RNA, Small Interfering - chemistry
RNA, Small Interfering - metabolism
Spinal Cord - metabolism
Superoxide Dismutase - genetics
Time Factors
Transgenes
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Many autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with copper/zinc superoxide dismutase (SOD1) mutation may be induced by missense point mutations that result in the production of proteins with toxic properties. Reduction in the encoding of proteins from such mutated genes can therefore be expected to improve the disease phenotype. The duplex of 21-nucleotide RNA, known as small interfering RNA (siRNA), has recently emerged as a powerful gene silencing tool. We made transgenic (Tg) mice with modified siRNA, which had multiple mismatch alternations within the sense strand, to prevent the “shutdown phenomenon” of transgenic siRNA. Consequently, the in vivo knockdown effect of siRNA on SOD1 expression did not diminish over four generations. When we crossed these anti-SOD1 siRNA Tg mice with SOD1G93A Tg mice, a model for ALS, siRNA prevented the development of disease by inhibiting mutant G93A SOD1 production in the central nervous system. Our findings clearly proved the principle that siRNA-mediated gene silencing can stop the development of familial ALS with SOD1 mutation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M507685200