Sigmar1, also known as the sigma-1 receptor, is a ubiquitously expressed multifunctional inter-organelle signaling chaperone protein [1]. It is enriched at the mitochondria-associated endoplasmic reticulum membrane (MAM) [2]. Sigmar1 contributes to numerous cellular functions, including ion channel regulation, protein quality control, endoplasmic reticulum-mitochondrial communication, lipid metabolism, mitochondrial function, autophagy activation, and is involved in cellular survival [1]. Alterations in its subcellular localization, expression, and signaling are implicated in a wide range of diseases [1]. The generation of Sigmar1 conditional knockout (Sigmar1loxP) mice using CRISPR-Cas9 provides a valuable tool for studying its tissue and cell-type-specific role [6].

Sigmar1 knockout (KO) mice and antagonist-pretreated mice exposed to methamphetamine showed higher blood pressure and more collagen deposition around vessels compared to wild-type mice exposed to methamphetamine, indicating that Sigmar1 is involved in methamphetamine-induced hypertension and vascular fibrosis by blocking the activation of the TGF-β/Smad2/3 signaling pathway [3]. In mouse retinal explants and cultured cells, Sigmar1 knockout impaired mitochondrial clearance without altering the PINK1-PRKN/Parkin signaling and compromised autophagosome-lysosome fusion, suggesting that Sigmar1 is important for autophagosome clearance [5]. In an ovariectomized mouse model, mice lacking Sigmar1 exhibited severe osteoporosis, while overexpression of Sigmar1 locally alleviated the osteoporosis phenotype, indicating that Sigmar1 is a negative regulator of osteoclastogenesis [4]. CdCl2 exposure in in vivo mouse models activated the SEL1L/HRD1-regulated endoplasmic reticulum-associated degradation (ERAD), enhancing the ubiquitin degradation of SigmaR1, and the administration of the SigmaR1 agonist ANAVEX2-73 rescued neurobehavioral inhibition and alleviated cellular senescence and AD-like pathology [7].

In conclusion, Sigmar1 plays essential roles in various biological processes such as autophagy, osteoclastogenesis, and regulation of blood pressure and vascular fibrosis. Sigmar1 KO/CKO mouse models have significantly contributed to understanding its role in neurodegenerative diseases like Alzheimer's disease, osteoporosis, and methamphetamine-induced hypertension, providing potential therapeutic targets for these disease areas.

References:

1. Aishwarya, Richa, Abdullah, Chowdhury S, Morshed, Mahboob, Remex, Naznin Sultana, Bhuiyan, Md Shenuarin. 2021. Sigmar1's Molecular, Cellular, and Biological Functions in Regulating Cellular Pathophysiology. In Frontiers in physiology, 12, 705575. doi:10.3389/fphys.2021.705575. https://pubmed.ncbi.nlm.nih.gov/34305655/

2. Couly, Simon, Yasui, Yuko, Su, Tsung-Ping. 2023. SIGMAR1 Confers Innate Resilience against Neurodegeneration. In International journal of molecular sciences, 24, . doi:10.3390/ijms24097767. https://pubmed.ncbi.nlm.nih.gov/37175473/

3. Xu, Zhen-Zhen, Zhou, Jie, Duan, Ke, Tao, Jing, Xie, Wei-Bing. 2024. Blocking Sigmar1 exacerbates methamphetamine-induced hypertension. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167284. doi:10.1016/j.bbadis.2024.167284. https://pubmed.ncbi.nlm.nih.gov/38851304/

4. Wei, Xiaoan, Zheng, Zeyu, Feng, Zhenhua, Chen, Jian, Zhao, Fengdong. 2022. Sigma-1 receptor attenuates osteoclastogenesis by promoting ER-associated degradation of SERCA2. In EMBO molecular medicine, 14, e15373. doi:10.15252/emmm.202115373. https://pubmed.ncbi.nlm.nih.gov/35611810/

5. Yang, Huan, Shen, Hongtao, Li, Jing, Guo, Lian-Wang. 2019. SIGMAR1/Sigma-1 receptor ablation impairs autophagosome clearance. In Autophagy, 15, 1539-1557. doi:10.1080/15548627.2019.1586248. https://pubmed.ncbi.nlm.nih.gov/30871407/

6. Huang, Liang, Xiao, Haiyan, Xie, Xiaoling, Smith, Sylvia B, Gan, Lin. 2022. Generation of Sigmar1 conditional knockout mouse using CRISPR-Cas9 gene targeting. In Genesis (New York, N.Y. : 2000), 60, e23487. doi:10.1002/dvg.23487. https://pubmed.ncbi.nlm.nih.gov/35633570/

7. Qian, Bo, Li, Ting-Yu, Zheng, Zhao-Xuan, Lin, Yu-Chun, Lin, Zhong-Ning. 2024. The involvement of SigmaR1K142 degradation mediated by ERAD in neural senescence linked with CdCl2 exposure. In Journal of hazardous materials, 472, 134466. doi:10.1016/j.jhazmat.2024.134466. https://pubmed.ncbi.nlm.nih.gov/38718507/