NmrA-like family domain containing 1 (NMRAL1), also known as HSCARG, is an NADP(H) sensor. It selectively binds to the reduced form of type II coenzyme NADPH via its Rossmann fold domain. In response to intracellular NADPH concentration changes, it can transform between homodimer and monomer, interacting with different binding partners. It is involved in multiple biological pathways, negatively regulating innate immunity by impairing the activities of NF-κB and RLR pathways, regulating redox homeostasis, and participating in the DNA damage response when translocated to the nucleus [1].

In schizophrenia research, a functional single-nucleotide polymorphism (rs2270363) at the 16p13.3 locus was found to disrupt the binding of certain proteins to the NMRAL1 promoter. The risk allele of rs2270363 was associated with elevated NMRAL1 expression in the human brain, yet NMRAL1 was significantly downregulated in the brains of schizophrenia patients. Knockdown of Nmral1 in mouse neural stem cells affected their proliferation, differentiation, and genes related to brain development and synaptic transmission, revealing its potential pathophysiological role in schizophrenia [2]. In ankylosing spondylitis (AS) patients with gut inflammation, NMRAL1 was identified as a key differentially expressed protein. Knockdown of NMRAL1 in murine macrophages significantly reduced the levels of key inflammatory cytokines, suggesting its potential role in the pathogenesis of AS and gut inflammation [3].

In conclusion, NMRAL1 is a crucial protein involved in multiple biological functions, including redox regulation, innate immunity, and DNA damage response. Studies using knockdown models in mice and cell lines have provided insights into its role in diseases such as schizophrenia and ankylosing spondylitis with gut inflammation, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Zang, Weicheng, Zheng, Xiaofeng. 2020. Structure and functions of cellular redox sensor HSCARG/NMRAL1, a linkage among redox status, innate immunity, DNA damage response, and cancer. In Free radical biology & medicine, 160, 768-774. doi:10.1016/j.freeradbiomed.2020.09.016. https://pubmed.ncbi.nlm.nih.gov/32950687/

2. Wang, Junyang, Li, Shiwu, Li, Xiaoyan, Xiao, Xiao, Luo, Xiong Jian. . Functional variant rs2270363 on 16p13.3 confers schizophrenia risk by regulating NMRAL1. In Brain : a journal of neurology, 145, 2569-2585. doi:10.1093/brain/awac020. https://pubmed.ncbi.nlm.nih.gov/35094059/

3. Cheng, Miao, Xiao, Siqi, Kayi, Shaer, Wang, Lei, He, Xiaojin. 2024. Colon mucosal proteomics of ankylosing spondylitis versus gut inflammation. In PloS one, 19, e0315324. doi:10.1371/journal.pone.0315324. https://pubmed.ncbi.nlm.nih.gov/39671362/