Search

Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients., Competing Interests: Declaration of competing interest R.C.S. has received research support and consultancy fees from Maze Therapeutics and is a member of the Medical Advisory Board for Little Warrior Foundation. M.S.G. has received research support, research compounds, or consultancy fees from Maze Therapeutics, Valerion Therapeutics, Ionis Pharmaceuticals, PTC Therapeutics, and the Glut1-Deficiency Syndrome Foundation. R.C.S. and M.S.G. are co-founders of Attrogen LLC. M.Corti has received research support from Sanofi, Friedreich Ataxia Research Alliance (FARA), Amicus, AavantiBio, Lacerta, Provention Bio, Sarepta, Duchenne Research Fund, Muscular Dystrophy Association (MDA), GoFAR, Cydan, Audentes. M.Corti has received consulting fees from AavantiBio, Reata, Lilly, Avexis and Gilbert foundation, SwanBio and PCT Therapeutics. B.J.B. has received research support from SolidBio, ProventionBio, Barth Syndrome Foundation. B.J.B. has received consulting fees from AavantiBio, Amicus Therapeutics, Rocket Pharma, Pfizer, Sanofi, and Sarepta Therapeutics. M.Corti and B.J.B. are co-founders of Ventura, LLC., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease., (© 2023. The Author(s).)

This chapter reviews the history of glycogen-related research and discusses in detail the structure, regulation, chemical properties and subcellular distribution of glycogen and its associated proteins, with particular focus on these aspects in brain tissue.

Glucan phosphatases are a family of enzymes that are functionally conserved at the enzymatic level in animals and plants. These enzymes bind and dephosphorylate glycogen in animals and starch in plants. While the enzymatic function is conserved, the glucan phosphatases employ distinct mechanisms to bind and dephosphorylate glycogen or starch. The founding member of the family is a bimodular human protein called laforin that is comprised of a carbohydrate binding module 20 (CBM20) followed by a dual specificity phosphatase domain. Plants contain two glucan phosphatases: Starch EXcess4 (SEX4) and Like Sex Four2 (LSF2). SEX4 contains a chloroplast targeting peptide, dual specificity phosphatase (DSP) domain, a CBM45, and a carboxy-terminal motif. LSF2 is comprised of simply a chloroplast targeting peptide, DSP domain, and carboxy-terminal motif. SEX4 employs an integrated DSP-CBM glucan-binding platform to engage and dephosphorylate starch. LSF2 lacks a CBM and instead utilizes two surface binding sites to bind and dephosphorylate starch. Laforin is a dimeric protein in solution and it utilizes a tetramodular architecture and cooperativity to bind and dephosphorylate glycogen. This chapter describes the biological role of glucan phosphatases in glycogen and starch metabolism and compares and contrasts their ability to bind and dephosphorylate glucans.