Abstract
Abnormal carbohydrate structures known as polyglucosan bodies (PGBs) are associated with neurological disorders, glycogen storage diseases (GSDs), and aging. A hallmark of the GSD Lafora disease (LD), a fatal childhood epilepsy caused by recessive mutations in the EPM2A or EPM2B genes, are cytoplasmic PGBs known as Lafora bodies (LBs). LBs result from aberrant glycogen metabolism and drive disease progression. They are abundant in brain, muscle and heart of LD patients and Epm2a-/- and Epm2b-/- mice. LBs and PGBs are histologically reminiscent of starch, semicrystalline carbohydrates synthesized for glucose storage in plants. In this study, we define LB architecture, tissue-specific differences, and dynamics. We propose a model for how small polyglucosans aggregate to form LBs. LBs are very similar to PGBs of aging and other neurological disorders, and so these studies have direct relevance to the general understanding of PGB structure and formation.
| Original language | English |
|---|---|
| Article number | 116260 |
| Journal | Carbohydrate Polymers |
| Volume | 240 |
| DOIs | |
| State | Published - Jul 15 2020 |
Bibliographical note
Publisher Copyright:© 2020 Elsevier Ltd
Funding
This work was supported by the National Institutes of Health [R01 NS070899 to M.S.G. P01 NS097197 to M.S.G. R35 NS116824 to M.S.G. F31 NS093892 to M.K.B.], an Epilepsy Foundation New Therapy Commercialization Grant to M.S.G. an award from the Mizutani Foundation for Glycoscience to M.S.G. and the Glyco@Alps program [ANR-15-IDEX-02]. M.K.B. has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sk?odowska-Curie grant agreement [No. 754510M]. M.A.S. is supported by a Mater Research McGuckin Early Career Fellowship, the University of Queensland's Amplify Initiative and Mater Foundation. We acknowledge the NanoBio-ICMG Platform (FR 2607, Grenoble, France) for granting access to the Electron Microscopy facility and Ziyi Wang for extracting the rat muscle glycogen, which was used as a reference sample for SEC. We also thank Xinle Tan for his technical assistance with SEC experiments, Robert Gilbert for providing access to SEC equipment, Dr. Carole Moncman, Dr. Thomas Wilkop and the UK Light Microscopy Core for technical support, and all members of the Gentry lab and Dr. Craig Vander Kooi for constructive discussions. This work was supported by the National Institutes of Health [ R01 NS070899 to M.S.G., P01 NS097197 to M.S.G., R35 NS116824 to M.S.G., F31 NS093892 to M.K.B.], an Epilepsy Foundation New Therapy Commercialization Grant to M.S.G., an award from the Mizutani Foundation for Glycoscience to M.S.G., and the Glyco@Alps program [ANR-15-IDEX-02]. M.K.B. has received funding from the European Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement [No. 754510M ]. M.A.S. is supported by a Mater Research McGuckin Early Career Fellowship , the University of Queensland\u2019s Amplify Initiative and Mater Foundation. We acknowledge the NanoBio-ICMG Platform (FR 2607, Grenoble, France) for granting access to the Electron Microscopy facility and Ziyi Wang for extracting the rat muscle glycogen, which was used as a reference sample for SEC. We also thank Xinle Tan for his technical assistance with SEC experiments, Robert Gilbert for providing access to SEC equipment, Dr. Carole Moncman, Dr. Thomas Wilkop and the UK Light Microscopy Core for technical support, and all members of the Gentry lab and Dr. Craig Vander Kooi for constructive discussions.
| Funders | Funder number |
|---|---|
| Epilepsy Foundation New Therapy Commercialization | |
| University of Queensland's Amplify Initiative | |
| University of Queensland’s Amplify Initiative | |
| Mater Research McGuckin | |
| Horizon 2020 | |
| Marie Skłodowska-Curie fellowship | 754510M |
| Mater Foundation | FR 2607 |
| Mater Foundation | |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | R01NS070899, R35NS116824, P01NS097197 |
| Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council | |
| National Institutes of Health (NIH) | F31 NS093892 |
| National Institutes of Health (NIH) | |
| Mizutani Foundation for Glycoscience | ANR-15-IDEX-02 |
| Mizutani Foundation for Glycoscience | |
| Horizon 2020 Framework Programme | 754510 |
| Horizon 2020 Framework Programme |
Keywords
- Lafora bodies
- Lafora disease
- epilepsy
- glycogen
- glycogen storage disease
- polyglucosan bodies
- starch
ASJC Scopus subject areas
- Organic Chemistry
- Polymers and Plastics
- Materials Chemistry