RESUMEN
Previous studies have indicated that the pathogenesis of amyotrophic lateral sclerosis (ALS) is closely linked to 5-hydroxytryptamine (5-HT). To investigate this further, we administered 5-HT receptor antagonists to SOD1*G93A transgenic (ALS mouse model) and wide-type mice. This involved intraperitoneal injections of either granisetron, piboserod, or ritanserin, which inhibit the 5-HT3, 5-HT4, and 5-HT2 receptors, respectively. The transgenic mice were found to have fewer 5-HT-positive cells in the spinal cord compared with wide-type mice. We found that the administration of granisetron reduced the body weight of the transgenic mice, while piboserod and ritanserin worsened the motor functioning, as assessed using a hanging wire test. However, none of the 5-HT receptor antagonists affected the disease progression. We analyzed the distribution and/or expression of TAR DNA binding protein 43 (TDP-43) and superoxide dismutase 1 G93A (SOD1-G93A), which form abnormal aggregates in ALS. We found that the expression of these proteins increased following the administration of all three 5-HT receptor antagonists. In addition, the disease-related mislocalization of TDP-43 to the cytoplasm increased markedly for all three drugs. In certain anatomical regions, the 5-HT receptor antagonists also led to a marked increase in the number of astrocytes and microglia and a decrease in the number of neurons. These results indicate that 5-HT deficiency may play a role in the pathogenesis of amyotrophic lateral sclerosis by inducing the abnormal expression and/or distribution of TDP-43 and SOD1-G93A and by activating glial cells. 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.
RESUMEN
Background: Nicotinamide adenine dinucleotide (NAD+) metabolism has drawn more attention on neurodegeneration research; however, the role in Amyotrophic Lateral Sclerosis (ALS) remains to be fully elucidated. Here, the purpose of this study was to investigate whether the circulating NAD+ metabolic-related gene signature could be identified as a reliable biomarker for ALS survival. Methods: A retrospective analysis of whole blood transcriptional profiles and clinical characteristics of 454 ALS patients was conducted in this study. A series of bioinformatics and machine-learning methods were combined to establish NAD+ metabolic-derived risk score (NPRS) to predict overall survival for ALS patients. The associations of clinical characteristic with NPRS were analyzed and compared. Receiver operating characteristic (ROC) and the calibration curve were utilized to assess the efficacy of prognostic model. Besides, the peripheral immune cell infiltration was assessed in different risk subgroups by applying the CIBERSORT algorithm. Results: Abnormal activation of the NAD+ metabolic pathway occurs in the peripheral blood of ALS patients. Four subtypes with distinct prognosis were constructed based on NAD+ metabolism-related gene expression patterns by using the consensus clustering method. A comparison of the expression profiles of genes related to NAD+ metabolism in different subtypes revealed that the synthase of NAD+ was closely associated with prognosis. Seventeen genes were selected to construct prognostic risk signature by LASSO regression. The NPRS exhibited stronger prognostic capacity compared to traditional clinic-pathological parameters. High NPRS was characterized by NAD+ metabolic exuberant with an unfavorable prognosis. The infiltration levels of several immune cells, such as CD4 naive T cells, CD8 T cells, neutrophils and macrophages, are significantly associated with NPRS. Further clinicopathological analysis revealed that NPRS is more appropriate for predicting the prognostic risk of patients with spinal onset. A prognostic nomogram exhibited more accurate survival prediction compared with other clinicopathological features. Conclusions: In conclusion, it was first proposed that the circulating NAD+ metabolism-derived gene signature is a promising biomarker to predict clinical outcomes, and ultimately facilitating the precise management of patients with ALS.