Li Zhao, Duan Jinhai, Cao AnQi, Gong Zhuo, Liu Hao, Shen Danyang, Ye Tonglin, Zhu Shunyan, Cen Qikai, He Shuaiying, He Yongqian, Zheng Canbing, Lin Xian
Department of Microsurgery, Orthopaedic Trauma and Hand Surgery, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, #58 Zhongshan 2nd Road, Guangzhou, Guangdong, China; Department of Anatomy &Physiology, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan 2nd Road, Guangzhou, Guangdong, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, #74, Zhongshan 2nd Road, Guangzhou, Guangdong, China.
Department of Geriatric Neurology, Guangdong Institute of Geriatrics, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, #106, Zhongshan, 2nd Road, Guanzhou, Guangdong, China.
Exp Neurol. 2025 Jun;388:115216. doi: 10.1016/j.expneurol.2025.115216. Epub 2025 Mar 13.
Parkinson's disease (PD) is the world's second most prevalent neurodegenerative disease. Currently, aside from levodopa, there are no other effective drugs clinically available to slow its progression. Otx2 plays a critical role in the differentiation of midbrain dopaminergic neurons (mDANs) during midbrain development. However, in adulthood, Otx2 is primarily expressed in the ventral tegmental area (VTA)-ventral part, and mDANs in the dorsal part of the VTA and the substantia nigra pars compacta (SNc) show no Otx2 expression. Research indicates that Otx2 is essential not only for the development of mDANs but also for their protection against the toxicity of MPTP and rotenone. Consequently, Otx2 is a potential clinical target for mDANs protection. Identifying the upstream mechanism that regulates Otx2 expression is crucial to restoring its expression in the SNc and enhancing its levels in the entire ventral midbrain mDANs. In this study, we have demonstrated the safety of Otx2 overexpression in vitro by using adeno-associate virus (AAV) and explored the feasibility of promoting Otx2 expression through the Wnt/β-Catenin signaling pathway using various drugs, a miR-34 mimic, and an inhibitor. Our results showed that Otx2 overexpression via AAV in the SNc is relatively safe, and CHIR99021 can induce Otx2 expression in mouse mDANs, thereby, alleviating PD-liked motor symptoms induced by MPTP. These findings suggest that modulating Otx2 expression through the Wnt/β-Catenin signaling pathway holds a therapeutic approach for Parkinson's disease.
帕金森病（PD）是世界上第二常见的神经退行性疾病。目前，除左旋多巴外，临床上没有其他有效的药物可减缓其进展。Otx2在中脑发育过程中对中脑多巴胺能神经元（mDANs）的分化起着关键作用。然而，在成年期，Otx2主要在腹侧被盖区（VTA）的腹侧部分表达，而VTA背侧部分和黑质致密部（SNc）的mDANs则不表达Otx2。研究表明，Otx2不仅对mDANs的发育至关重要，而且对其抵抗MPTP和鱼藤酮的毒性也至关重要。因此，Otx2是保护mDANs的潜在临床靶点。确定调节Otx2表达的上游机制对于恢复其在SNc中的表达并提高整个腹侧中脑mDANs中的水平至关重要。在本研究中，我们通过使用腺相关病毒（AAV）在体外证明了Otx2过表达的安全性，并探索了使用各种药物、miR-34模拟物和抑制剂通过Wnt/β-连环蛋白信号通路促进Otx2表达的可行性。我们的结果表明，通过AAV在SNc中过表达Otx2相对安全，CHIR99021可以诱导小鼠mDANs中Otx2的表达，从而减轻MPTP诱导的帕金森病样运动症状。这些发现表明，通过Wnt/β-连环蛋白信号通路调节Otx2表达是一种治疗帕金森病的方法。
