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Deficiency of the E3 Ubiquitin Ligase RBCK1 Causes Diffuse Brain Polyglucosan Accumulation and Neurodegeneration

Authors :
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
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.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....de9c5e6cd2df8cccc6a673ffc341fb8f
Full Text :
https://doi.org/10.1101/277392