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Deficiency of the E3 Ubiquitin Ligase RBCK1 Causes Diffuse Brain Polyglucosan Accumulation and Neurodegeneration
- Publication Year :
- 2018
- Publisher :
- Cold Spring Harbor Laboratory, 2018.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....de9c5e6cd2df8cccc6a673ffc341fb8f
- Full Text :
- https://doi.org/10.1101/277392