Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors
Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors
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DOI：
10.1016/j.ymthe.2022.11.018
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发表时间：
2023-03-01
影响因子：
12.4
通讯作者：
Harada，Takayuki
中科院分区：
文献类型：
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作者：
Nishijima，Euido;Honda，Sari;Harada，Takayuki
神经营养因子信号的激活是神经变性的一种有前途的疗法。然而，配体依赖性激活的瞬时性质限制了其有效性。在这项研究中，我们解决了这个问题，发明了一个系统，迫使膜定位的细胞内结构域的原肌球蛋白受体激酶B（iTrk B），这导致组成型激活没有配体。我们的系统克服了腺相关病毒（AAV）中基因组包装的小尺寸限制，并允许转基因的高表达。在眼睛中使用AAV介导的基因治疗，我们证明iTrkB表达增强了青光眼小鼠模型的神经保护作用，并刺激视神经损伤后的轴突再生。此外，视网膜中的iTrkB表达在视束横断模型中也是有效的，其中损伤部位靠近上级丘。再生的轴突成功地形成了通往大脑目标的通路，导致视觉行为的部分恢复。我们的系统也可能适用于其他营养因子信号通路，并导致神经创伤和神经退行性疾病，包括青光眼的基因治疗领域的重大进展。
Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, the transient nature of ligand-dependent activation limits its effectiveness. In this study, we solved this problem by inventing a system that forces membrane localization of the intracellular domain of tropomyosin receptor kinase B (iTrkB), which results in constitutive activation without ligands. Our system overcomes the small size limitation of the genome packaging in adeno-associated virus (AAV) and allows high expression of the transgene. Using AAV-mediated gene therapy in the eyes, we demonstrate that iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after optic nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which the injury site is near the superior colliculus. Regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behavior. Our system may also be applicable to other trophic factor signaling pathways and lead to a significant advance in the field of gene therapy for neurotrauma and neurodegenerative disorders, including glaucoma.