Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice

✍ Scribed by Bradley J. Turner; Simon S. Murray; Loretta G. Piccenna; Elizabeth C. Lopes; Trevor J. Kilpatrick; Surindar S. Cheema

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 203 KB
• Volume: 78
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.20256

✦ Synopsis

Abstract

Neurotrophin level imbalances and altered p75 neurotrophin receptor (p75^NTR^) expression are implicated in spinal motor neuron degeneration in human and mouse models of amyotrophic lateral sclerosis (ALS). Recently, elevated reactive astrocyte‐derived nerve growth factor (NGF) was linked to p75^NTR^‐expressing motor neuron death in adult transgenic ALS mice. To test the role of NGF‐dependent p75^NTR^‐mediated signalling in ALS, we examined the effects of a cyclic decapeptide antagonist of p75^NTR^ ligand binding by using neurotrophin‐stimulated cell death assays and transgenic ALS mice. Murine motor neuron‐like (NSC‐34) cell cultures expressed full‐length and truncated p75^NTR^, tyrosine receptor kinase B (TrkB), and the novel neurotrophin receptor homolog‐2 (NHR2) but were TrkA deficient. Accordingly, treatment of cells with NGF induced dose‐dependent cell death, which was significantly blocked by the cyclic decapeptide p75^NTR^ antagonist. Application of brain‐derived neurotrophic factor, neurotrophin‐3, or neurotrophin‐4 to cultures increased cell proliferation, and such trophic effects were abolished by pretreatment with the tyrosine kinase inhibitor K‐252a. Systemic administration of a modified cyclic decapeptide p75^NTR^ antagonist conjugated to the TAT4 cell permeabilization sequence to presymptomatic transgenic SOD1^G93A^ mice affected neither disease onset nor disease progression, as determined by hindlimb locomotor, grip strength, and survival analyses. These studies suggest that disrupting NGF‐p75^NTR^ interactions by using this approach is insufficient to alter the disease course in transgenic ALS mice. Thus, alternate ligand‐independent pathways of p75^NTR^ activation or additional NGF receptor targets may contribute to motor neuron degeneration in ALS mice. © 2004 Wiley‐Liss, Inc.