Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice

Turner, B, Cheah, I, KJ,, Lopes, E, Petratos, S, Langford, S and Cheema, S 2003, 'Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice', Journal of Neurochemistry, vol. 87, no. 3, pp. 752-763.


Document type: Journal Article
Collection: Journal Articles

Title Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice
Author(s) Turner, B
Cheah, I
KJ,
Lopes, E
Petratos, S
Langford, S
Cheema, S
Year 2003
Journal name Journal of Neurochemistry
Volume number 87
Issue number 3
Start page 752
End page 763
Total pages 12
Publisher Wiley-Blackwell Publishing Ltd.
Abstract Re-expression of the death-signalling p75 neurotrophin receptor (p75 NTR) is associated with injury and neurodegeneration in the adult nervous system. The induction of p75NTR expression in mature degenerating spinal motor neurons of humans and transgenic mice with amyotrophic lateral sclerosis (ALS) suggests a role of p75 NTR in the progression of motor neuron disease (MND). In this study, we designed, synthesized and evaluated novel antisense peptide nucleic acid (PNA) constructs targeting p75NTR as a potential gene knockdown therapeutic strategy for ALS. An 11 -mer antisense PNA directed at the initiation codon, but not downstream gene sequences, dose-dependently inhibited p75NTR expression and death-signalling by nerve growth factor (NGF) in Schwann cell cultures. Antisense phosphorothioate oligonucleotide (PS-ODN) sequences used for comparison failed to confer such inhibitory activity. Systemic intraperitoneal administration of this antisense PNA to mutant superoxide dismutase 1 (SOD1G93A) transgenic mice significantly delayed locomotor impairment and mortality compared with mice injected with nonsense or scrambled PNA sequences. Reductions in p75NTR expression and subsequent caspase-3 activation in spinal cords were consistent with increased survival in antisense PNA-treated mice. The uptake of fluorescent-labelled antisense PNA in the nervous system of transgenic mice was also confirmed. This study suggests that p75NTR may be a promising antisense target in the treatment of ALS.
Keyword(s) amyotrophic lateral sclerosis
antisense
motor neuron
p75 neurotrophin receptor
peptide nucleic acid
superoxide dismutase 1
DOI - identifier 10.1046/j.1471-4159.2003.02053.x
ISSN 0022-3042
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