2. Academic Validation
  3. Knockdown of OPTN modulates miRNA-125b-5p expression via NF-κB pathways in amyotrophic lateral sclerosis

Knockdown of OPTN modulates miRNA-125b-5p expression via NF-κB pathways in amyotrophic lateral sclerosis

  • Arch Biochem Biophys. 2025 Sep:771:110499. doi: 10.1016/j.abb.2025.110499.
Jian Qin 1,  Ye He 2,  Weiyi Yu 3,  Zhaoyong Zhang 4,  Xiaodan Chen 5,  Yafang Hu 6,  Haishan Jiang 7
Affiliations

Affiliations

  • 1 Nanfang Hospital, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong, China. Electronic address: 850848256@qq.com.
  • 2 Nanfang Hospital, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong, China. Electronic address: yeyeyeho@126.com.
  • 3 Nanfang Hospital, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong, China; Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou 510260, Guangdong, China. Electronic address: asdem1028@126.com.
  • 4 Nanfang Hospital, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong, China. Electronic address: gdpnzhangzy@163.com.
  • 5 Nanfang Hospital, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong, China. Electronic address: 2635925073@qq.com.
  • 6 Nanfang Hospital, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong, China. Electronic address: yafanghu@smu.edu.cn.
  • 7 Nanfang Hospital, Southern Medical University, No.1023, South Shatai Road, Baiyun District, Guangzhou, Guangdong, China. Electronic address: jianghs@smu.edu.cn.
PMID: 40482989 DOI: 10.1016/j.abb.2025.110499
Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterized by severe dysfunction in upper and lower motor neurons. Previous studies have reported that the optineurin gene (OPTN) downregulation is one of the causative genetic factors for ALS, leading to the dysfunction of optineurin (OPTN), a multifunctional protein implicated in several cellular processes. Herein, we found that conditional knockout of the Optn gene in mouse microglia leads to activation of microglia. In subsequent studies, we also found that OPTN knockdown in BV2 cells leads to the activation of BV2 cells and promotes the Apoptosis of co-cultured NSC34 cells via exosomes derived from BV2 cells in vitro. In contrast, OPTN knockdown in NSC34 cells did not cause Apoptosis of the NSC34 cells themselves. It was suggested that microglia activation is involved in ALS initiation and development, but the nature of microglial-neuronal interactions remained elusive, requiring further exploration. Exosomes have been proven to be essential mediators. Notably, increased miRNA-125b-5p expression was uncovered in BV2 cells with the OPTN gene silenced, their derived exosomes, as well as the cocultured NSC34 cells. Interestingly, we proved that increased miRNA-125b-5p enhanced the Apoptosis of NSC34 cells. We further noted that the overexpression of miRNA-125b-5p in BV2 cells can be regulated by an NF-κB Activator (LPS) or inhibitor (withaferin A). Altogether, this study showed that silencing the OPTN gene may overexpress miRNA-125b-5p levels via the classical NF-κB pathway in BV2 cells. Up-regulated miRNA-125b-5p might be transmitted from exosomes to NSC34 cells, resulting in NSC34 cells Apoptosis. Microglial-neuronal interactions mediated by exosomes were the crucial mechanism of OPTN gene downregulation leading to ALS, and this conclusion had been verified in cell models.

Keywords

Amyotrophic lateral sclerosis; Exosome; Microglia activation; NF-κB pathway; Optineurin; miRNA.

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