Death of injured neurons caused by the precursor of nerve growth factor

Because the adult mammalian brain has a very limited capacity to replace neurons lost after lesion (1), understanding the mechanisms regulating their survival or elimination is of special significance. A study in this issue of PNAS (2) reveals that cutting the axons of a neuronal population involved in movement control leads to a progressive and dramatic increase of pro-nerve growth factor (NGF) in brain fluids. Pro-NGF kills injured neurons by virtue of its high affinity binding to a receptor that is induced after axotomy, the neurotrophin receptor p75. Another recent study also indicates that neurons may not be the only targets of pro-NGF-mediated killing: after partial transaction of the spinal cord, oligodendrocytes may also be eliminated by the mechanism described by Harrington and colleagues (3). In mammals, the neurotrophin family consists of four genes that encode structurally related proteins that are proteolytically processed and secreted in the extracellular space (for review, see ref. 4). In the brain, the secretion of neurotrophins is regulated by the activity of the neurons that synthesize them, and after secretion, these proteins affect many important aspects of neuronal function, including synaptic transmission and excitability (for review, see ref. 5). As their names suggest, neurotrophins are best known for their “trophic” roles on neurons, typically including the promotion of nerve growth and the prevention of the death of embryonic neurons. These two properties were used to purify NGF and brain-derived neurotrophic factor (BDNF), respectively (for review, see ref. 4). Protein sequencing work revealed that the activity of these two neurotrophins is contained in what was shown by cDNA cloning to correspond to …