Deficiency of the E3 Ubiquitin Ligase RBCK1 Causes Diffuse Brain Polyglucosan Accumulation and Neurodegeneration
| Autor: | Ami M. Perri, Saija Ahonen, Xiaochu Zhao, Lori Israelian, Felix Nitschke, Cameron Ackerley, Berge A. Minassian, Mitchell A. Sullivan, Sharmistha Mitra, Laura F. DiGiovanni, Erin E. Chown, Mackenzie Chown, Peixiang Wang |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0303 health sciences
biology Glycogen Hyperphosphorylation medicine.disease Lafora disease Ubiquitin ligase Cell biology Glycogen Branching Enzyme Deficiency 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine chemistry Glycogen branching enzyme biology.protein medicine Glycogen synthase Laforin 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/277392 |
| Popis: | SUMMARYGlycogen synthesis is vital, malstructure resulting in precipitation and accumulation into neurotoxic polyglucosan bodies (PBs). One well-understood mechanism of PB generation is glycogen branching enzyme deficiency (GBED). Less understood is Lafora disease (LD), resulting from absence of the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, and accumulation of hyperphosphorylated PBs. LD afforded first insight that glycogen sphericity depends on more than adequate branching activity. Unexpectedly, deficiencies of the Linear Ubiquitin Chain Assembly Complex (LUBAC) components RBCK1 and HOIP result in PBs in muscle tissues. Here we analyzed nervous system phenotypes of mice lacking RBCK1 and find profuse PB accumulations in brain and spinal cord with extensive neurodegeneration and neurobehavioral deficits. Brain glycogen in these mice is characterized by long chains and hyperphosphorylation, similar to LD. Like in LD, glycogen synthase and branching enzyme are unaltered. Regional PB distribution mirrors LD and not GBED. Perisynaptic PB localization is unlike LD or GBED. The results indicate that RBCK1 is part of a system supplementing laforin-malin in regulating glycogen architecture including in unique neuronal locales. |
| Databáze: | OpenAIRE |
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