p75 neurotrophin receptor signaling in nervous system injury and degeneration: paradox and opportunity.
ABSTRACT Injury or insult to the adult nervous system often results in reactivation of signaling pathways that are normally only active during development. The p75 neurotrophin receptor (p75(NTR)) is one such signaling molecule whose expression increases markedly following neural injury in many of the same cell types that express p75(NTR) during development. A series of studies during the past decade has demonstrated that p75(NTR) signaling contributes to neuronal and glial cell damage, axonal degeneration and dysfunction during injury and cellular stress. Why the nervous system reacts to injury by inducing a molecule that aids the demise of cells and axons is a biological paradox that remains to be explained satisfactorily. On the other hand, it may offer unique therapeutic opportunities for limiting the severity of nervous system injury and disease.
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ABSTRACT: When Clostridium tetani was discovered and identified as a Gram-positive anaerobic bacterium of the genus Clostridium, the possibility of turning its toxin into a valuable biological carrier to ameliorate neurodegenerative processes was inconceivable. However, the non-toxic carboxy-terminal fragment of the tetanus toxin heavy chain (fragment C) can be retrogradely transported to the central nervous system; therefore, fragment C has been used as a valuable biological carrier of neurotrophic factors to ameliorate neurodegenerative processes. More recently, the neuroprotective properties of fragment C have also been described in vitro and in vivo, involving the activation of Akt kinase and extracellular signal-regulated kinase (ERK) signaling cascades through neurotrophin tyrosine kinase (Trk) receptors. Although the precise mechanism of the molecular internalization of fragment C in neuronal cells remains unknown, fragment C could be internalized and translocated into the neuronal cytosol through a clathrin-mediated pathway dependent on proteins, such as dynamin and AP-2. In this review, the origins, molecular properties and possible signaling pathways of fragment C are reviewed to understand the biochemical characteristics of its intracellular and synaptic transport.International Journal of Molecular Sciences 01/2012; 13(6):6883-901. · 2.46 Impact Factor