Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency

• 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. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

Nyckelord

antisense oligonucleotide (ASO) therapy

glycogen synthase

neuroinflammation

PGBM1 (polyglucosan body myopathy 1)

RBCK1/HOIL1

1

4 alpha glucan branching enzyme

amylopectin

glucan

glycogen

hydroxyl group

phosphatase

ubiquitin

ubiquitin protein ligase E3

non receptor protein tyrosine phosphatase

ubiquitin protein ligase

animal experiment

animal model

Article

cardiac muscle

controlled study

down regulation

enzyme deficiency

female

gait

glycogen muscle level

glycogen storage disease type 4

grip strength

histology

male

motor neuron disease

mouse

myoclonus epilepsy

nervous system inflammation

nonhuman

nonsense mediated mRNA decay

open field test

physical chemistry

protein depletion

rotarod test

spinal cord

animal

genetics

glycogen storage disease

mammal

metabolism

neurologic disease

pathology

Animals

Down-Regulation

Glucans

Glycogen Storage Disease Type IV

Lafora Disease

Mammals

Mice

Myoclonic Epilepsies

Progressive

Nervous System Diseases

Protein Tyrosine Phosphatases

Non-Receptor

Ubiquitin-Protein Ligases

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)