Journal article
Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency
Brain , Vol.145(7), pp.2361-2377
2022
PMID: 35084461
Abstract
Longer glucan chains tend to precipitate. Glycogen, by far the largest mammalian glucan and the largest molecule in the cytosol with up to 55 000 glucoses, does not, due to a highly regularly branched spherical structure that allows it to be perfused with cytosol. Aberrant construction of glycogen leads it to precipitate, accumulate into polyglucosan bodies that resemble plant starch amylopectin and cause disease. This pathology, amylopectinosis, is caused by mutations in a series of single genes whose functions are under active study toward understanding the mechanisms of proper glycogen construction. Concurrently, we are characterizing the physicochemical particularities of glycogen and polyglucosans associated with each gene. These genes include GBE1, EPM2A and EPM2B, which respectively encode the glycogen branching enzyme, the glycogen phosphatase laforin and the laforin-interacting E3 ubiquitin ligase malin, for which an unequivocal function is not yet known. Mutations in GBE1 cause a motor neuron disease (adult polyglucosan body disease), and mutations in EPM2A or EPM2B a fatal progressive myoclonus epilepsy (Lafora disease). RBCK1 deficiency causes an amylopectinosis with fatal skeletal and cardiac myopathy (polyglucosan body myopathy 1, OMIM# 615895). RBCK1 is a component of the linear ubiquitin chain assembly complex, with unique functions including generating linear ubiquitin chains and ubiquitinating hydroxyl (versus canonical amine) residues, including of glycogen.
In a mouse model we now show (i) that the amylopectinosis of RBCK1 deficiency, like in adult polyglucosan body disease and Lafora disease, affects the brain; (ii) that RBCK1 deficiency glycogen, like in adult polyglucosan body disease and Lafora disease, has overlong branches; (iii) that unlike adult polyglucosan body disease but like Lafora disease, RBCK1 deficiency glycogen is hyperphosphorylated; and finally (iv) that unlike laforin-deficient Lafora disease but like malin-deficient Lafora disease, RBCK1 deficiency’s glycogen hyperphosphorylation is limited to precipitated polyglucosans.
In summary, the fundamental glycogen pathology of RBCK1 deficiency recapitulates that of malin-deficient Lafora disease. Additionally, we uncover sex and genetic background effects in RBCK1 deficiency on organ- and brain-region specific amylopectinoses, and in the brain on consequent neuroinflammation and behavioural deficits. Finally, we exploit the portion of the basic glycogen pathology that is common to adult polyglucosan body disease, both forms of Lafora disease and RBCK1 deficiency, namely overlong branches, to show that a unified approach based on downregulating glycogen synthase, the enzyme that elongates glycogen branches, can rescue all four diseases.
Details
- Title
- Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency
- Authors
- Silvia Nitschke - Hospital for Sick ChildrenMitchell A Sullivan - Hospital for Sick ChildrenSharmistha Mitra - The University of Texas Southwestern Medical CenterCharlotte R Marchioni - The University of Texas Southwestern Medical CenterJennifer P.Y. Lee - Hospital for Sick ChildrenBrandon H Smith - The University of Texas Southwestern Medical CenterSaija Ahonen - Hospital for Sick ChildrenJun Wu - The University of Texas Southwestern Medical CenterErin E Chown - Hospital for Sick ChildrenPeixiang Wang - Hospital for Sick ChildrenSara Petković - Hospital for Sick ChildrenXiaochu Zhao - Hospital for Sick ChildrenLaura F DiGiovanni - Hospital for Sick ChildrenAmi M Perri - Hospital for Sick ChildrenLori Israelian - Hospital for Sick ChildrenTamar R Grossman - Ionis PharmaceuticalsHolly Kordasiewicz - Ionis PharmaceuticalsFrancisco Vilaplana - KTH Royal Institute of TechnologyKazuhiro Iwai - Kyoto UniversityFelix Nitschke (Corresponding Author) - Hospital for Sick ChildrenBerge A Minassian (Corresponding Author) - Hospital for Sick Children
- Publication details
- Brain , Vol.145(7), pp.2361-2377
- Publisher
- Oxford University Press
- Date published
- 2022
- DOI
- 10.1093/brain/awac017
- ISSN
- 1460-2156
- PMID
- 35084461
- Grant note
- This work was funded by the National Institute of Neurological Disorders and Stroke under award number P01NS097197.
- Organisation Unit
- School of Health - Biomedicine
- Language
- English
- Record Identifier
- 991035093402621
- Output Type
- Journal article
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