<i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease
Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the <i>GLA</i> gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and...
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2024-03-01
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| author | Ping Li Yuqian Xi Yanping Zhang Abdus Samad Wenli Lan Ya Wu Jiayu Zhao Guangxin Chen Changxin Wu Qiuhong Xiong |
| author_facet | Ping Li Yuqian Xi Yanping Zhang Abdus Samad Wenli Lan Ya Wu Jiayu Zhao Guangxin Chen Changxin Wu Qiuhong Xiong |
| author_sort | Ping Li |
| collection | DOAJ |
| description | Fabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the <i>GLA</i> gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and central nervous system. In our previous study, we identified four <i>GLA</i> mutations from four independent Fabry disease families with kidney disease or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) and c.801+1G>A (p.L268fsX3). To reveal the molecular mechanism underlying the predisposition to Fabry disease caused by <i>GLA</i> mutations, we analyzed the effects of these four <i>GLA</i> mutations on the protein structure of α-galactosidase A using bioinformatics methods. The results showed that these mutations have a significant impact on the internal dynamics and structures of GLA, and all these altered amino acids are close to the enzyme activity center and lead to significantly reduced enzyme activity. Furthermore, these mutations led to the accumulation of autophagosomes and impairment of autophagy in the cells, which may in turn negatively regulate autophagy by slightly increasing the phosphorylation of mTOR. Moreover, the overexpression of these GLA mutants promoted the expression of lysosome-associated membrane protein 2 (LAMP2), resulting in an increased number of lysosomes. Our study reveals the pathogenesis of these four <i>GLA</i> mutations in FD and provides a scientific foundation for accurate diagnosis and precise medical intervention for FD. |
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| spelling | doaj.art-8d41cb62fc7f43f9b3c572a9210ad03e2024-03-12T16:41:43ZengMDPI AGCells2073-44092024-03-0113543710.3390/cells13050437<i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry DiseasePing Li0Yuqian Xi1Yanping Zhang2Abdus Samad3Wenli Lan4Ya Wu5Jiayu Zhao6Guangxin Chen7Changxin Wu8Qiuhong Xiong9Institutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaDepartment of Biochemistry, Abdul Wali Khan University Mardan, Mardan 23200, PakistanInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaInstitutes of Biomedical Sciences, The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education of China, The Key Laboratory of Medical Molecular Cell Biology of Shanxi Province, Shanxi University, Taiyuan 030006, ChinaFabry disease (FD) is an X-linked recessive inheritance lysosomal storage disorder caused by pathogenic mutations in the <i>GLA</i> gene leading to a deficiency of the enzyme alpha-galactosidase A (α-Gal A). Multiple organ systems are implicated in FD, most notably the kidney, heart, and central nervous system. In our previous study, we identified four <i>GLA</i> mutations from four independent Fabry disease families with kidney disease or neuropathic pain: c.119C>A (p.P40H), c.280T>C (C94R), c.680G>C (p.R227P) and c.801+1G>A (p.L268fsX3). To reveal the molecular mechanism underlying the predisposition to Fabry disease caused by <i>GLA</i> mutations, we analyzed the effects of these four <i>GLA</i> mutations on the protein structure of α-galactosidase A using bioinformatics methods. The results showed that these mutations have a significant impact on the internal dynamics and structures of GLA, and all these altered amino acids are close to the enzyme activity center and lead to significantly reduced enzyme activity. Furthermore, these mutations led to the accumulation of autophagosomes and impairment of autophagy in the cells, which may in turn negatively regulate autophagy by slightly increasing the phosphorylation of mTOR. Moreover, the overexpression of these GLA mutants promoted the expression of lysosome-associated membrane protein 2 (LAMP2), resulting in an increased number of lysosomes. Our study reveals the pathogenesis of these four <i>GLA</i> mutations in FD and provides a scientific foundation for accurate diagnosis and precise medical intervention for FD.https://www.mdpi.com/2073-4409/13/5/437fabry diseasekidneyGLAautophagylysosomemTOR |
| spellingShingle | Ping Li Yuqian Xi Yanping Zhang Abdus Samad Wenli Lan Ya Wu Jiayu Zhao Guangxin Chen Changxin Wu Qiuhong Xiong <i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease Cells fabry disease kidney GLA autophagy lysosome mTOR |
| title | <i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease |
| title_full | <i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease |
| title_fullStr | <i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease |
| title_full_unstemmed | <i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease |
| title_short | <i>GLA</i> Mutations Suppress Autophagy and Stimulate Lysosome Generation in Fabry Disease |
| title_sort | i gla i mutations suppress autophagy and stimulate lysosome generation in fabry disease |
| topic | fabry disease kidney GLA autophagy lysosome mTOR |
| url | https://www.mdpi.com/2073-4409/13/5/437 |
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