Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Effect of p75 neurotrophin receptor antagonist on disease progression in transgenic amyotrophic lateral sclerosis mice. 1537 12