Premium
Antisense peptide nucleic acid‐mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice
Author(s) -
Turner Bradley J.,
Cheah Irwin K.,
Macfarlane Katherine J.,
Lopes Elizabeth C.,
Petratos Steven,
Langford Steven J.,
Cheema Surindar S.
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02053.x
Subject(s) - gene knockdown , biology , transgene , genetically modified mouse , microbiology and biotechnology , neurotrophin , motor neuron , low affinity nerve growth factor receptor , neurodegeneration , sod1 , sense (electronics) , receptor , mutant , apoptosis , chemistry , gene , biochemistry , medicine , neuroscience , spinal cord , disease
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 p75 NTR 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 p75 NTR 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 p75 NTR 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 (SOD1 G93A ) transgenic mice significantly delayed locomotor impairment and mortality compared with mice injected with nonsense or scrambled PNA sequences. Reductions in p75 NTR 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 p75 NTR may be a promising antisense target in the treatment of ALS.