Transactivation of Trk receptors in spinal motor neurons.

The neurotrophins are a family of trophic factors that have been shown to have neuroprotective effects after traumatic lesions of the nervous system and in animal models of neurodegenerative diseases. They mediate a broad spectrum of biological actions by interacting with tyrosine kinase receptors (Trk). While studies have demonstrated that neurotrophin administration may have beneficial effects, there were difficulties in delivering therapeutic quantities of these factors to spinal motor neurons. We now describe a strategy for applying transactivation of Trk receptors using small molecules, such as adenosine, which can penetrate the blood brain barrier and rescue motor neurons from cell death. Transactivation opens up the possibility of stimulating Trk receptors only in populations of neurons that co-express both Trk and adenosine receptors. We propose in this review to exploit transactivation to improve the survival of motor neurons in a transgenic mouse model of ALS and for other neurodegenerative diseases, such as Alzheimer's and Huntington's disease.

MAG induces regulated intramembrane proteolysis of the p75 neurotrophin receptor to inhibit neurite outgrowth.

The three known inhibitors of axonal regeneration present in myelin--MAG, Nogo, and OMgp--all interact with the same receptor complex to effect inhibition via protein kinase C (PKC)-dependent activation of the small GTPase Rho. The transducing component of this receptor complex is the p75 neurotrophin receptor. Here we show that MAG binding to cerebellar neurons induces alpha- and then gamma-secretase proteolytic cleavage of p75, in a protein kinase C-dependent manner, and that this cleavage is necessary for both activation of Rho and inhibition of neurite outgrowth.