| Summary: | 博士 === 國立清華大學 === 生醫工程與環境科學系 === 105 === Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by the deficiency of survival motor neuron (SMN) protein. There are majorly four types of SMA with different disease severities, and the specific mechanism of SMA is unclear. SMN2 copy number is considered as the major modifier in SMA. This study firstly conducted a pilot study in microarray analysis of six human blood samples to elucidate that SMA types had more influence than SMN2 copy number on SMA, and indicate the existence of other modifiers regulating for the phenotype of SMA. Therefore, this study further established an integrative transcriptomic analysis using human microarray tissue samples from microarray databases to identify the potential SMA target genes relevant to disease severity, and the efficacy of a candidate medicine worked on the targets was evaluated in a severe type of SMA mouse model.
The 39 human microarray datasets across different types of SMA tissues were used to construct an integrative transcriptomic analysis for recognizing novel target genes of SMA potentially regulating disease severity. This analysis was mainly conducted with the weighted correlation network analysis (WGCNA) along with Cytoscape network reconstruction to identify three regulation pathways associated with disease severity including TNFα-BMP4-SERPINE1-GATA6 (neural and cardiac development), TNFα-PTGS2-BCL2 (skeletal development), and TNFα-IL6-CNTN1 (nervous system development). The analysis of receiver operating characteristic (ROC) curve showed that TNFα-BMP4-SERPINE1-GATA6 pathway had the highest accuracy in SMA status (AUC = 0.8864), which meant that the down-regulation of up-stream gene BMP4 may be one of the key points in SMA pathogenesis. Previous studies have indicated that expression of BMP4 can be induced by a cholesterol lowering drug atorvastatin. Therefore, atorvastatin was chosen as the candidate medicine and evaluated its efficacy for SMA mice.
Daily intraperitoneally atorvastatin treatment (2.5, 5, and 10 mg/kg/day) prolonged the lifespan, increased body weight, and improved motor coordination in SMA mice (Smn−/−SMN2+/−). SMA mice receiving atorvastatin treatment for 8 days exhibited reduced motor neuron degeneration and muscle and cardiac atrophy as compared to control littermates. The expression of Bmp4 was significantly up-regulated but human SMN2 gene was not in spinal cord, muscular and heart tissues in SMA mice treated with atorvastatin. In conclusion, atorvastatin treatment modified biological and behavioral deficits in SMA mice potentially via up-regulation of Bmp4 expression, indicating the critical role of BMP4 in SMA treatment.
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