Regulation of NR4A2 Gene Expression and Its Importance in Neurodegenerative and Psychiatric Diseases

Nuclear receptor subfamily 4 group A member 2 (NR4A2) is a transcription factor that regulates the expression of different genes involved in essential biological processes, including cell proliferation, neuronal development, immune response, cellular stress, apoptosis, DNA repair, and angiogenesis. The gene encoding this transcription factor is called NR4A2 and has been identified as an immediate early gene. Moreover, research in animal models and clinical trials has suggested an association between reduced NR4A2 gene expression and some neurodegenerative diseases and psychiatric disorders. These include Parkinson's disease, Alzheimer's disease progression, schizophrenia, substance abuse (alcohol and amphetamines), neurodevelopmental disorders, and cognitive imairment. NR4A2 activity is controlled at multiple levels, including transcriptional and post-transcriptional regulation of its gene expression, such as translational and post-translational processes. This review summarizes the current knowledge of the NR4A2 gene, encompassing its structure and the molecular mechanisms that regulate its expression. The key epigenetic mechanisms that regulate its gene expression are emphasized, including DNA methylation, histone deacetylation, and regulation by microRNAs. It also addresses its role in central nervous system pathologies associated with dysregulation of NR4A2 gene expression. Finally, we discuss the potential of these regulatory mechanisms as biomarkers and therapeutic targets for neurodegenerative diseases and psychiatric disorders.