Rao Mishal, Luo Ziming, Liu Chia-Chun, Chen Chi-Yu, Wang Shining, Nahmou Michael, Tanasa Bogdan, Virmani Aman, Byrne Leah, Goldberg Jeffrey L, Sahel José-Alain, Chang Kun-Che
Department of Ophthalmology, UPMC Vision Institute, University of Pittsburgh School of Medicine, 1622 Locust Street, Pittsburgh, PA, 15219, USA.
Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA, 94305, USA.
Acta Neuropathol Commun. 2024 Dec 29;12(1):204. doi: 10.1186/s40478-024-01917-6.
Mammalian central nervous system (CNS) axons cannot spontaneously regenerate after injury, creating an unmet need to identify molecular regulators to promote axon regeneration and reduce the lasting impact of CNS injuries. While tubulin polymerization promoting protein family member 3 (Tppp3) is known to promote axon outgrowth in amphibians, its role in mammalian axon regeneration remains unknown. Here we investigated Tppp3 in retinal ganglion cells (RGCs) neuroprotection and axonal regeneration using an optic nerve crush (ONC) model in the rodent. Single-cell RNA sequencing identified the expression of Tppp3 in RGCs of mice, macaques, and humans. Tppp3 overexpression enhanced neurite outgrowth in mouse primary RGCs in vitro, promoted axon regeneration, and improved RGC survival after ONC. Bulk RNA sequencing indicated that Tppp3 overexpression upregulates axon regeneration genes such as Bmp4 and neuroinflammatory pathways. Our findings advance regenerative medicine by developing a new therapeutic strategy for RGC neuroprotection and axon regeneration.
哺乳动物中枢神经系统（CNS）轴突在损伤后无法自发再生，因此迫切需要确定促进轴突再生的分子调节因子，以减轻CNS损伤的长期影响。虽然已知微管蛋白聚合促进蛋白家族成员3（Tppp3）可促进两栖动物的轴突生长，但其在哺乳动物轴突再生中的作用尚不清楚。在这里，我们使用啮齿动物的视神经挤压（ONC）模型研究了Tppp3在视网膜神经节细胞（RGC）神经保护和轴突再生中的作用。单细胞RNA测序确定了Tppp3在小鼠、猕猴和人类的RGC中的表达。Tppp3过表达增强了小鼠原代RGC在体外的神经突生长，促进了轴突再生，并改善了ONC后的RGC存活。批量RNA测序表明，Tppp3过表达上调了轴突再生基因，如Bmp4和神经炎症通路。我们的研究结果通过开发一种新的RGC神经保护和轴突再生治疗策略，推动了再生医学的发展。
