中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (10): 2293-2299.doi: 10.4103/1673-5374.337051

• 原著:退行性病与再生 • 上一篇    下一篇

SARM1可参与朊病毒疾病中轴突变性和线粒体功能障碍

  

  • 出版日期:2022-10-15 发布日期:2022-03-16
  • 基金资助:
    中国国家自然科学基金项目(31972641);国家重点研发计划项目(2017YFC1200500)

SARM1 participates in axonal degeneration and mitochondrial dysfunction in prion disease

Meng-Yu Lai, Jie Li, Xi-Xi Zhang, Wei Wu, Zhi-Ping Li, Zhi-Xin Sun, Meng-Yang Zhao, Dong-Ming Yang, Dong-Dong Wang, Wen Li, De-Ming Zhao, Xiang-Mei Zhou, Li-Feng Yang   

  1. National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, China
  • Online:2022-10-15 Published:2022-03-16
  • Contact: Li-Feng Yang, PhD, yanglf@cau.edu.cn; Xiang-Mei Zhou, PhD, zhouxm@cau.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 31972641 and the National Key Research and Development Program of China, No. 2017YFC1200500 (both to LFY).

摘要:

与许多其他神经退行性疾病一样,朊病毒疾病是一类与能量损失、轴突变性和线粒体功能障碍相关的致命人类和动物疾病。轴突变性是朊病毒疾病神经变性的早期标志,而SARM1是触发这一病理过程的蛋白。实验发现SARM1耗竭或功能障碍突变可防止PrP106-126诱导的NAD+缺失、轴突变性和线粒体功能障碍。补充NAD+可挽救朊病毒引发的轴突变性和线粒体功能障碍,而SARM1过表达则抑制了这种保护作用。在PrP106-126干预的N2a细胞中补充NAD+、耗竭SARM1或表达和功能失调的SARM1(S548A)突变均会阻止神经元凋亡并提高细胞存活率。上述结果提示,由PrP106-126神经毒性肽引发的轴索变性和线粒体功能障碍部分依赖于SARM1的NADase活性,因而SARM1有望成为治疗朊病毒疾病的潜在靶点。

https://orcid.org/0000-0001-5175-7589 (Li-Feng Yang); https://orcid.org/0000-0003-1566-5745 (Xiang-Mei Zhou)

关键词: 朊病毒疾病, 神经退行性疾病, 轴突退变, 线粒体功能障碍, SARM1, NAD+代谢, NAD酶

Abstract: Prion disease represents a group of fatal neurogenerative diseases in humans and animals that are associated with energy loss, axonal degeneration, and mitochondrial dysfunction. Axonal degeneration is an early hallmark of neurodegeneration and is triggered by SARM1. We found that depletion or dysfunctional mutation of SARM1 protected against NAD+ loss, axonal degeneration, and mitochondrial functional disorder induced by the neurotoxic peptide PrP106–126. NAD+ supplementation rescued prion-triggered axonal degeneration and mitochondrial dysfunction and SARM1 overexpression suppressed this protective effect. NAD+ supplementation in PrP106–126-incubated N2a cells, SARM1 depletion, and SARM1 dysfunctional mutation each blocked neuronal apoptosis and increased cell survival. Our results indicate that the axonal degeneration and mitochondrial dysfunction triggered by PrP106–126 are partially dependent on SARM1 NADase activity. This pathway has potential as a therapeutic target in the early stages of prion disease.

Key words: axonal degeneration, mitochondrial dysfunction, NAD+ metabolism, NADase, neurodegenerative disease, prion disease, SARM1, sterile alpha and TIR motif-containing 1