Nitration and Glycation Turn Mature NGF into a Toxic Factor for Motor Neurons: A Role for p75NTR and RAGE Signaling in ALS

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.

Our results indicate that NGF-RAGE/p75NTR signaling may be a therapeutic target in ALS. Antioxid. Redox Signal. 28, 1587-1602.

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.