The neurotrophin growth factors bind and activate two types of cell surface receptors: the tropomyosin receptor kinase (Trk) family and p75. TrkA, TrkB, and TrkC are bound preferentially by nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 (NT3), respectively, 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 with mutant D, mutant RK, and wild-type 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.

中文翻译：

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选择性激活原肌球蛋白受体激酶 (Trk) 家族神经营养因子受体而非 p75 神经营养因子受体的工程神经营养因子的治疗性神经保护作用

神经营养因子生长因子结合并激活两种类型的细胞表面受体：原肌球蛋白受体激酶 (Trk) 家族和 p75。TrkA、TrkB 和 TrkC 分别优先与神经生长因子、脑源性神经营养因子和神经营养因子 3 (NT3) 结合，以激活神经保护信号。p75 受体被所有神经营养因子激活，矛盾的是在神经退行性疾病中 p75 被上调并介导神经毒性信号。为了测试神经保护策略，我们设计了 NT3 以广泛激活 Trk 受体（突变体 D）或减少 p75 结合（突变体 RK）。我们还在激活 TrkA、TrkB 和 TrkC 但降低 p75 结合（突变 DRK）的分子中结合了这些特征。在体内神经退行性疾病小鼠模型中，与突变体 D 相比，DRK 蛋白是一种优越的治疗剂，突变体 RK 和野生型神经营养因子，并保护更广泛的受压神经元。这项工作使基于每种受体生物学的治疗策略合理化，避免激活 p75 毒性，同时广泛激活表达不同 Trk 受体的受压神经元群的神经保护。