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.

Background/Objectives: Several genetic factors are related to the risk of Alzheimer’s disease (AD) and the response to cholinesterase inhibitors (ChEIs) (donepezil, galantamine, and rivastigmine) or memantine. However, findings have been controversial, and, to the best of our knowledge, admixed populations have not been previously evaluated. We aimed to determine the impact of genetic and non-genetic factors on the risk of AD and the short-term response to ChEIs and memantine in patients with AD from Mexico. Methods: This study included 117 patients from two specialty hospitals in Mexico City, Mexico. We evaluated cognitive performance via clinical evaluations and neuropsychological tests. Nineteen variants in ABCB1, ACHE, APOE, BCHE, CHAT, CYP2D6, CYP3A5, CHRNA7, NR1I2, and POR were assessed through TaqMan assays or PCR. Results: Minor alleles of the ABCB1 rs1045642, ACHE rs17884589, and CHAT rs2177370 and rs3793790 variants were associated with the risk of AD; meanwhile, CHRNA7 rs6494223 and CYP3A5 rs776746 were identified as low-risk variants in AD. BCHE rs1803274 was associated with worse cognitive functioning. None of the genetic and non-genetic factors studied were associated with the response to pharmacological treatment. Conclusions: We identified potential genetic variants related to the risk of AD; meanwhile, no factor was observed to impact the response to pharmacological therapy in patients with AD from Mexico.

Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressing, fatal neurodegenerative disorder that selectively affects motor neurons. Clinical manifestations include progressive muscle weakness, amyotrophy, fasciculations, dysphagia, and fatal respiratory failure. The median survival after symptom onset is typically 2 to 5 years. Despite its severity, the epidemiological profile and genetic landscape of ALS in Latin American populations, particularly in Mexico, remain unclear. In this study, we evaluated the mutational spectrum of the SOD1 gene in a Mexican cohort of 156 ALS patients. Using high-resolution melting (HRM) analysis and Sanger sequencing, we identified 22 SOD1 variants in 42 of 156 patients (overall variant carrier frequency, 26.92%). Pathogenic or likely pathogenic (P/LP) variants were found in 21 patients (13.5%). Notably, 5 of the 22 variants were novel, expanding the spectrum of SOD1 variants. The variant carrier frequency identified in this study is higher than that reported for European populations but similar to frequencies observed in Asian populations. Our results highlight the distinct genetic heterogeneity of ALS in Mexico and demonstrate that HRM is a rapid and effective method for identifying SOD1 gene variants.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder that selectively affects motor neurons. The median survival time after diagnosis is 2 to 5 years. Oxidative stress (OS), driven mainly by reactive oxygen species (ROS), plays a central role in motor neuron (MN) degeneration. In this narrative review, we analyse the pathogenic role of SOD1 variants and their contribution to OS in ALS. SOD1 mutations alter the Cu/Zn superoxide dismutase enzyme, thereby promoting oxidative damage and triggering neuroinflammatory cascades via the MAPK, NF-κB and Nrf2/ARE signalling pathways. We also discuss emerging proteomic and machine-learning biomarkers, as well as the current therapeutic landscape. Riluzole and edaravone are approved treatments, while AMX0035 was approved in 2022 but withdrawn in 2024. Masitinib and EPI-589 remain investigational. In the realm of genetic therapies, the antisense oligonucleotide tofersen received accelerated FDA approval in 2023 for SOD1-ALS, primarily due to its ability to reduce plasma neurofilament light chain levels. However, the clinical benefit remains modest. RNA interference has reached human trials, while CRISPR/Cas9 remains in the preclinical stage. Both approaches have shown promising results in experimental models. Further research into ALS pathogenesis is needed to develop treatments that integrate antioxidant, anti-inflammatory, and gene-editing strategies.