The neurotrophin growth factors bind and activate two types of cell surface receptors: the Trk family, and p75. TrkA, TrkB or TrkC are bound preferentially by NGF, BDNF, or NT3 to activate neuroprotective signals. The p75 receptors are activated by all neurotrophins, and paradoxically in neurodegenerative disease p75 is upregulated and mediates neurotoxic signals. To test neuroprotection strategies, we engineered NT3 to broadly activate Trk receptors (mutant D), or to reduce p75 binding (mutant RK). We also combined these features in a molecule that activates TrkA, TrkB and TrkC but has reduced p75 binding (mutant DRK). In neurodegenerative disease mouse models in vivo, the DRK protein is a superior therapeutic agent compared to D, to RK, or to wildtype neurotrophins, and protects a broader range of stressed neurons. This work rationalizes a therapeutic strategy based on the biology of each type of receptor, avoiding activation of p75 toxicity while broadly activating neuroprotection in stressed neuronal populations expressing different Trk receptors.
Significance Statement.Neurotrophins NGF BDNF and NT3 growth factors, each can activate a TrkA or TrkB or TrkC receptor respectively, and all can activate a p75 receptor. Trks and p75 mediate opposite signals. We report the engineering of a protein that activates all Trks, combined with low p75 binding, as an effective therapeutic agent in vivo.