Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease
Abstract Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss‐of‐function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bo...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201707608 |
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| author | Felix Nitschke Mitchell A Sullivan Peixiang Wang Xiaochu Zhao Erin E Chown Ami M Perri Lori Israelian Lucia Juana‐López Paola Bovolenta Santiago Rodríguez de Córdoba Martin Steup Berge A Minassian |
| author_facet | Felix Nitschke Mitchell A Sullivan Peixiang Wang Xiaochu Zhao Erin E Chown Ami M Perri Lori Israelian Lucia Juana‐López Paola Bovolenta Santiago Rodríguez de Córdoba Martin Steup Berge A Minassian |
| author_sort | Felix Nitschke |
| collection | DOAJ |
| description | Abstract Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss‐of‐function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase‐inactive laforin rescues the laforin‐deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin‐ or malin‐deficient mouse lines expressing phosphatase‐inactive laforin. We find that: (i) in laforin‐deficient mice, phosphatase‐inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin‐deficient mice, phosphatase‐inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD. We conclude that laforin's principle function is to control glycogen chain lengths, in a malin‐dependent fashion, and that loss of this control underlies LD. |
| format | Article |
| id | doaj-art-a2b1331cf25e4a71adbb2ac75bba0a1b |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a2b1331cf25e4a71adbb2ac75bba0a1b2025-08-20T04:02:56ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-05-019790691710.15252/emmm.201707608Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora diseaseFelix Nitschke0Mitchell A Sullivan1Peixiang Wang2Xiaochu Zhao3Erin E Chown4Ami M Perri5Lori Israelian6Lucia Juana‐López7Paola Bovolenta8Santiago Rodríguez de Córdoba9Martin Steup10Berge A Minassian11Program in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteCentro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Ciber de Enfermedades RarasCentro de Biología Molecular Severo Ochoa, CSIC‐UAM and Ciber de Enfermedades Raras, Universidad Autónoma de MadridCentro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Ciber de Enfermedades RarasProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteProgram in Genetics and Genome Biology, The Hospital for Sick Children Research InstituteAbstract Lafora disease (LD) is a fatal progressive epilepsy essentially caused by loss‐of‐function mutations in the glycogen phosphatase laforin or the ubiquitin E3 ligase malin. Glycogen in LD is hyperphosphorylated and poorly hydrosoluble. It precipitates and accumulates into neurotoxic Lafora bodies (LBs). The leading LD hypothesis that hyperphosphorylation causes the insolubility was recently challenged by the observation that phosphatase‐inactive laforin rescues the laforin‐deficient LD mouse model, apparently through correction of a general autophagy impairment. We were for the first time able to quantify brain glycogen phosphate. We also measured glycogen content and chain lengths, LBs, and autophagy markers in several laforin‐ or malin‐deficient mouse lines expressing phosphatase‐inactive laforin. We find that: (i) in laforin‐deficient mice, phosphatase‐inactive laforin corrects glycogen chain lengths, and not hyperphosphorylation, which leads to correction of glycogen amounts and prevention of LBs; (ii) in malin‐deficient mice, phosphatase‐inactive laforin confers no correction; (iii) general impairment of autophagy is not necessary in LD. We conclude that laforin's principle function is to control glycogen chain lengths, in a malin‐dependent fashion, and that loss of this control underlies LD.https://doi.org/10.15252/emmm.201707608glycogen chain lengthglycogen phosphorylationLafora diseaselaforinmalin |
| spellingShingle | Felix Nitschke Mitchell A Sullivan Peixiang Wang Xiaochu Zhao Erin E Chown Ami M Perri Lori Israelian Lucia Juana‐López Paola Bovolenta Santiago Rodríguez de Córdoba Martin Steup Berge A Minassian Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease EMBO Molecular Medicine glycogen chain length glycogen phosphorylation Lafora disease laforin malin |
| title | Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease |
| title_full | Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease |
| title_fullStr | Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease |
| title_full_unstemmed | Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease |
| title_short | Abnormal glycogen chain length pattern, not hyperphosphorylation, is critical in Lafora disease |
| title_sort | abnormal glycogen chain length pattern not hyperphosphorylation is critical in lafora disease |
| topic | glycogen chain length glycogen phosphorylation Lafora disease laforin malin |
| url | https://doi.org/10.15252/emmm.201707608 |
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