Salbutamol inhibits ubiquitin-mediated survival motor neuron protein degradation in spinal muscular atrophy cells |
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Authors: | Nur Imma Fatimah Harahap Dian Kesumapramudya Nurputra Mawaddah Ar Rochmah Ai Shima Naoya Morisada Toru Takarada Atsuko Takeuchi Yumi Tohyama Shinichiro Yanagisawa Hisahide Nishio |
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Institution: | 1. Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan;2. Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan;3. Analytical Center, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higasinada-ku, Kobe Pharmaceutical University, Kobe 658-8558, Japan;4. Division of Biochemistry, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiono, Himeji 670-8524, Japan;5. Division of Medical Economics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, 7-2-1 Kamiono, Himeji 670-8524, Japan |
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Abstract: | Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is currently incurable. SMA is caused by decreased levels of the survival motor neuron protein (SMN), as a result of loss or mutation of SMN1. Although the SMN1 homolog SMN2 also produces some SMN protein, it does not fully compensate for the loss or dysfunction of SMN1. Salbutamol, a β2-adrenergic receptor agonist and well-known bronchodilator used in asthma patients, has recently been shown to ameliorate symptoms in SMA patients. However, the precise mechanism of salbutamol action is unclear. We treated SMA fibroblast cells lacking SMN1 and HeLa cells with salbutamol and analyzed SMN2 mRNA and SMN protein levels in SMA fibroblasts, and changes in SMN protein ubiquitination in HeLa cells. Salbutamol increased SMN protein levels in a dose-dependent manner in SMA fibroblast cells lacking SMN1, though no significant changes in SMN2 mRNA levels were observed. Notably, the salbutamol-induced increase in SMN was blocked by a protein kinase A (PKA) inhibitor and deubiquitinase inhibitor, respectively. Co-immunoprecipitation assay using HeLa cells showed that ubiquitinated SMN levels decreased in the presence of salbutamol, suggesting that salbutamol inhibited ubiquitination. The results of this study suggest that salbutamol may increase SMN protein levels in SMA by inhibiting ubiquitin-mediated SMN degradation via activating β2-adrenergic receptor-PKA pathways. |
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Keywords: | Spinal muscular atrophy Survival motor neuron gene Salbutamol Survival motor neuron protein Ubiquitination |
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