Neurotensin: A new role in the prevention of neuronal cell death following peripheral nerve injury?

Abstract

Nerve injury resulting from trauma frequently leads to loss of function due to neuronal degeneration and cell death. The molecular mechanisms involved in neuronal cell death are poorly understood, but are thought to parallel apoptosis, or programmed cell death. Several new molecules have been identified as key players involved in the induction of neuronal cell death. Sortilin, a recently discovered receptor expressed in neuronal tissues, has been shown to collaborate with the p75 neurotrophin receptor (p75NTR) and induce apoptosis in neurons upon binding of unprocessed nerve growth factor, also known as proNGF. Sortilin also functions as a receptor for the peptide neurotransmitter neurotensin. ProNGF-activation of the p75NTR apoptotic signaling cascade can be prevented by neurotensin binding to the sortilin receptor, thereby blocking the binding of proNGF to the sortilin-p75NTR receptor complex (Nykjaer et al., 2004). We have recently demonstrated that neurotensin expression is dramatically increased in the mouse dorsal root ganglia (DRG) following peripheral nerve injury. Taken together, these data suggest a neuroprotective role for neurotensin in preventing neuronal cell death following injury. To test the hypothesis that neurotensin plays an important role in neuronal survival following nerve injury, current studies are underway to assess neuronal cell survival in the DRG, seven days following peripheral nerve injury amongst mice which are null-mutant, heterozygous, or wild-type for the neurotensin gene. Interference in the binding of proNGF to the sortilin-p75NTR receptor complex using neurotensin may provide a therapeutic approach for the treatment of disorders involving neuronal loss.