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

Turner, Bradley J. ; Cheah, Irwin K. ; Macfarlane, Katherine J. ; Lopes, Elizabeth C. ; Petratos, Steven ; Langford, Steven J. ; Cheema, Surindar S.

Journal of neurochemistry, 2003-11, Vol.87 (3), p.752-763 [Periódico revisado por pares]

Oxford, UK: Blackwell Science Ltd

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Título:
Antisense peptide nucleic acid‐mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice
Autor: Turner, Bradley J. ; Cheah, Irwin K. ; Macfarlane, Katherine J. ; Lopes, Elizabeth C. ; Petratos, Steven ; Langford, Steven J. ; Cheema, Surindar S.
Assuntos: amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - therapy ; Animals ; antisense ; Biological and medical sciences ; Caspase 3 ; Caspases - biosynthesis ; Cells, Cultured ; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases ; Disease Models, Animal ; Disease Progression ; Fluorescent Dyes ; Genetic Therapy - methods ; Medical sciences ; Mice ; Mice, Transgenic ; motor neuron ; Nerve Growth Factor - pharmacology ; Neurology ; Oligonucleotides, Antisense - pharmacology ; p75 neurotrophin receptor ; peptide nucleic acid ; Peptide Nucleic Acids - pharmacokinetics ; Peptide Nucleic Acids - pharmacology ; Rats ; Rats, Wistar ; Receptor, Nerve Growth Factor ; Receptors, Nerve Growth Factor - antagonists & inhibitors ; Receptors, Nerve Growth Factor - biosynthesis ; Receptors, Nerve Growth Factor - genetics ; Schwann Cells - cytology ; Schwann Cells - drug effects ; Schwann Cells - metabolism ; Signal Transduction - drug effects ; Superoxide Dismutase - genetics ; superoxide dismutase 1
É parte de: Journal of neurochemistry, 2003-11, Vol.87 (3), p.752-763
Notas: ObjectType-Article-2
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Descrição: Re‐expression of the death‐signalling p75 neurotrophin receptor (p75NTR) 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 p75NTR 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.
Editor: Oxford, UK: Blackwell Science Ltd
Idioma: Inglês

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

Turner, Bradley J. ; Cheah, Irwin K. ; Macfarlane, Katherine J. ; Lopes, Elizabeth C. ; Petratos, Steven ; Langford, Steven J. ; Cheema, Surindar S.

Oxford, UK: Blackwell Science Ltd

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