Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2
Details
State: Public
Version: Final published version
License: Not specified
It was possible to publish this article open access thanks to a Swiss National Licence with the publisher.
Serval ID
serval:BIB_F4FBC793D3AB
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Increased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2
Journal
Human Molecular Genetics
ISSN
0964-6906 (Print)
Publication state
Published
Issued date
03/2000
Volume
9
Number
5
Pages
803-11
Notes
Journal Article
Research Support, Non-U.S. Gov't --- Old month value: Mar 22
Research Support, Non-U.S. Gov't --- Old month value: Mar 22
Abstract
Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie some familial cases of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by loss of cortical, brainstem and spinal motoneurons. Transgenic mice over- expressing a mutated form of human SOD1 containing a Gly-->Ala substitution at position 93 (SOD1(G93A)) develop a severe, progressive motoneuron disease. We investigated the potential of recombinant adeno-associated virus (rAAV) to transfer neuroprotective molecules in this animal ALS model. Initial experiments showed that injection of an rAAV vector encoding green fluorescent protein unilaterally into the lumbar spinal cord of wild-type mice leads to expression of the reporter gene in 34.7 +/- 5.2% of the motoneurons surrounding the injection site. Intraspinal injection of an rAAV encoding the anti-apoptotic protein bcl-2 in SOD1 (G93A) mice resulted in sustained bcl-2 expression in motoneurons and significantly increased the number of surviving motoneurons at the end-stage of disease. Moreover, the compound muscle action potential amplitude elicited by nerve stimulation and recorded by electromyographic measurements was higher in the rAAV-bcl-2-treated group than in controls. Local bcl-2 expression in spinal motoneurons delayed the appearance of signs of motor deficiency but was not sufficient to prolong the survival of SOD1 (G93A) mice. To our know-ledge, this study describes the first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease. Our results support the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance motoneuron survival and repair.
Keywords
Animals
Base Sequence
Cell Survival
DNA Primers
Dependovirus/*genetics
Genes, bcl-2
Humans
Injections, Spinal
Mice
Mice, Inbred C57BL
Mice, Transgenic
Motor Neurons/*cytology
Muscles/cytology/*innervation/physiology
Transduction, Genetic
Pubmed
Web of science
Open Access
Yes
Create date
28/01/2008 9:44
Last modification date
14/02/2022 8:57