Nitration and Glycation Turn Mature NGF into a Toxic Factor for Motor Neurons: A Role for p75NTRand RAGE Signaling in ALS

Introduction: Glycating stress can occur together with oxidative stress during neurodegeneration and contribute to the pathogenic mechanism. Nerve growth factor (NGF) accumulates in several neurodegenerative diseases. Besides promoting survival, NGF can paradoxically induce cell death by signaling through the p75 neurotrophin receptor (p75NTR). The ability of NGF to induce cell death is increased by nitration of its tyrosine residues under conditions associated with increased peroxynitrite formation. Aims: Here we investigated whether glycation also changes the ability of NGF to induce cell death and assessed the ability of post-translational modified NGF to signal through the receptor for advanced glycation end products (RAGEs). We also explored the potential role of RAGE–p75NTR interaction in the motor neuron death occurring in amyotrophic lateral sclerosis (ALS) models. Results: Glycation promoted NGF oligomerization and ultimately allowed the modified neurotrophin to signal through RAGE and p75NTR to induce motor neuron death at low physiological concentrations. A similar mechanism was observed for nitrated NGF. We provide evidence for the interaction of RAGE with p75NTR at the cell surface. Moreover, we observed that post-translational modified NGF was present in the spinal cord of an ALS mouse model. In addition, NGF signaling through RAGE and p75NTR was involved in astrocyte-mediated motor neuron toxicity, a pathogenic feature of ALS. Innovation: Oxidative modifications occurring under stress conditions can enhance the ability of mature NGF to induce neuronal death at physiologically relevant concentrations, and RAGE is a new p75NTR coreceptor contributing to this pathway. Conclusion: Our results indicate that NGF–RAGE/p75NTR signaling may be a therapeutic target in ALS. Antioxid. Redox Signal. 28, 1587–1602.