Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS
Abstract A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria‐associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM...
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Springer Nature
2016-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606403 |
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| author | Seiji Watanabe Hristelina Ilieva Hiromi Tamada Hanae Nomura Okiru Komine Fumito Endo Shijie Jin Pedro Mancias Hiroshi Kiyama Koji Yamanaka |
| author_facet | Seiji Watanabe Hristelina Ilieva Hiromi Tamada Hanae Nomura Okiru Komine Fumito Endo Shijie Jin Pedro Mancias Hiroshi Kiyama Koji Yamanaka |
| author_sort | Seiji Watanabe |
| collection | DOAJ |
| description | Abstract A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria‐associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS‐linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5‐triphosphate receptor type 3 (IP3R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)‐mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP3R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R‐ and SOD1‐linked ALS. Furthermore, our discovery of the selective enrichment of IP3R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS. |
| format | Article |
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| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-11-01 |
| publisher | Springer Nature |
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| series | EMBO Molecular Medicine |
| spelling | doaj-art-5a0e8df1db3c421faba5a9e7e0a8319f2025-08-20T03:46:24ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-11-018121421143710.15252/emmm.201606403Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALSSeiji Watanabe0Hristelina Ilieva1Hiromi Tamada2Hanae Nomura3Okiru Komine4Fumito Endo5Shijie Jin6Pedro Mancias7Hiroshi Kiyama8Koji Yamanaka9Department of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityHouston Methodist HospitalDepartment of Functional Anatomy and Neuroscience, Nagoya University Graduate School of MedicineDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityDepartment of Pediatrics, The University of Texas Medical School at HoustonDepartment of Functional Anatomy and Neuroscience, Nagoya University Graduate School of MedicineDepartment of Neuroscience and Pathobiology, Research Institute of Environmental Medicine, Nagoya UniversityAbstract A homozygous mutation in the gene for sigma 1 receptor (Sig1R) is a cause of inherited juvenile amyotrophic lateral sclerosis (ALS16). Sig1R localizes to the mitochondria‐associated membrane (MAM), which is an interface of mitochondria and endoplasmic reticulum. However, the role of the MAM in ALS is not fully elucidated. Here, we identified a homozygous p.L95fs mutation of Sig1R as a novel cause of ALS16. ALS‐linked Sig1R variants were unstable and incapable of binding to inositol 1,4,5‐triphosphate receptor type 3 (IP3R3). The onset of mutant Cu/Zn superoxide dismutase (SOD1)‐mediated ALS disease in mice was accelerated when Sig1R was deficient. Moreover, either deficiency of Sig1R or accumulation of mutant SOD1 induced MAM disruption, resulting in mislocalization of IP3R3 from the MAM, calpain activation, and mitochondrial dysfunction. Our findings indicate that a loss of Sig1R function is causative for ALS16, and collapse of the MAM is a common pathomechanism in both Sig1R‐ and SOD1‐linked ALS. Furthermore, our discovery of the selective enrichment of IP3R3 in motor neurons suggests that integrity of the MAM is crucial for the selective vulnerability in ALS.https://doi.org/10.15252/emmm.201606403amyotrophic lateral sclerosisinositol 1,4,5‐triphosphate receptor type 3mitochondria‐associated membranesigma 1 receptor |
| spellingShingle | Seiji Watanabe Hristelina Ilieva Hiromi Tamada Hanae Nomura Okiru Komine Fumito Endo Shijie Jin Pedro Mancias Hiroshi Kiyama Koji Yamanaka Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS EMBO Molecular Medicine amyotrophic lateral sclerosis inositol 1,4,5‐triphosphate receptor type 3 mitochondria‐associated membrane sigma 1 receptor |
| title | Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS |
| title_full | Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS |
| title_fullStr | Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS |
| title_full_unstemmed | Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS |
| title_short | Mitochondria‐associated membrane collapse is a common pathomechanism in SIGMAR1‐ and SOD1‐linked ALS |
| title_sort | mitochondria associated membrane collapse is a common pathomechanism in sigmar1 and sod1 linked als |
| topic | amyotrophic lateral sclerosis inositol 1,4,5‐triphosphate receptor type 3 mitochondria‐associated membrane sigma 1 receptor |
| url | https://doi.org/10.15252/emmm.201606403 |
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