glycogen and Neurodegenerative-Diseases

Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads to accumulation of poorly branched glycogen known as polyglucosan. GSD IV is characterized by a remarkable degree of phenotypic heterogeneity with presentations in utero, during infancy, early childhood, adolescence, or middle to late adulthood. The clinical continuum encompasses hepatic, cardiac, muscular, and neurologic manifestations that range in severity. The adult-onset form of GSD IV, referred to as adult polyglucosan body disease (APBD), is a neurodegenerative disease characterized by neurogenic bladder, spastic paraparesis, and peripheral neuropathy. There are currently no consensus guidelines for the diagnosis and management of these patients, resulting in high rates of misdiagnosis, delayed diagnosis, and lack of standardized clinical care. To address this, a group of experts from the United States developed a set of recommendations for the diagnosis and management of all clinical phenotypes of GSD IV, including APBD, to support clinicians and caregivers who provide long-term care for individuals with GSD IV. The educational resource includes practical steps to confirm a GSD IV diagnosis and best practices for medical management, including (a) imaging of the liver, heart, skeletal muscle, brain, and spine, (b) functional and neuromusculoskeletal assessments, (c) laboratory investigations, (d) liver and heart transplantation, and (e) long-term follow-up care. Remaining knowledge gaps are detailed to emphasize areas for improvement and future research.

Topics: Child, Preschool; Glycogen; Glycogen Storage Disease; Glycogen Storage Disease Type IV; Humans; Neurodegenerative Diseases

Access to metabolic information in vivo using magnetic resonance (MR) technologies has generally been the niche of MR spectroscopy (MRS) and spectroscopic imaging (MRSI). Metabolic fluxes can be studied using the infusion of substrates labeled with magnetic isotopes, with the use of hyperpolarization especially powerful. Unfortunately, these promising methods are not yet accepted clinically, where fast, simple, and reliable measurement and diagnosis are key. Recent advances in functional MRI and chemical exchange saturation transfer (CEST) MRI allow the use of water imaging to study oxygen metabolism and tissue metabolite levels. These, together with the use of novel data analysis approaches such as machine learning for all of these metabolic MR approaches, are increasing the likelihood of their clinical translation.

Topics: Animals; Brain; Carbon Isotopes; Contrast Media; Creatine; Deep Learning; Glycogen; Humans; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Muscles; Neurodegenerative Diseases; Oxygen; Positron-Emission Tomography

Emerging evidence that autophagy serves as a sweeper for toxic materials in the brain gives us new insight into the pathophysiology of neurodegenerative diseases. Autophagy is important for maintaining cellular homeostasis associated with metabolism. Some neurodegenerative diseases such as Alzheimer׳s and Parkinson׳s diseases are accompanied by altered metabolism and autophagy in the brain. In this review, we discuss how hormones and nutrients regulate autophagy in the brain and affect neurodegeneration. This article is part of a Special Issue entitled SI:Autophagy.

Topics: Alzheimer Disease; Animals; Autophagy; Brain; Cholesterol; Ghrelin; Glucose; Glycogen; Homeostasis; Humans; Inulin; Melatonin; Mice; Neurodegenerative Diseases; Parkinson Disease

Topics: Adaptor Proteins, Signal Transducing; Adult; Autism Spectrum Disorder; Autophagy; Autophagy-Related Proteins; Carrier Proteins; Endoplasmic Reticulum; Flavoproteins; Frontotemporal Dementia; Glycogen; Humans; Lysosomes; Nerve Tissue Proteins; Neurodegenerative Diseases; Phosphoric Monoester Hydrolases; Proteins; rab3 GTP-Binding Proteins; Vacuolar Proton-Translocating ATPases; Vesicular Transport Proteins

Dithiocarbamates (DTCs) are important industrial chemicals used extensively as pesticides and in a variety of therapeutic applications. However, they have also been associated with neurotoxic effects and in particular with the development of Parkinson-like neuropathy. Although different pathways and enzymes (such as ubiquitin ligases or the proteasome) have been identified as potential targets of DTCs in the brain, the molecular mechanisms underlying their neurotoxicity remain poorly understood. There is increasing evidence that alteration of glycogen metabolism in the brain contributes to neurodegenerative processes. Interestingly, recent studies with N,N-diethyldithiocarbamate suggest that brain glycogen phosphorylase (bGP) and glycogen metabolism could be altered by DTCs. Here, we provide molecular and mechanistic evidence that bGP is a target of DTCs. To examine this system, we first tested thiram, a DTC pesticide known to display neurotoxic effects, observing that it can react rapidly with bGP and readily inhibits its glycogenolytic activity (k

Topics: Glycogen; Glycogen Phosphorylase, Brain Form; Humans; Neurodegenerative Diseases; Neurotoxicity Syndromes; Neurotoxins; Thiocarbamates

Under physiological conditions, most neurons keep glycogen synthase (GS) in an inactive form and do not show detectable levels of glycogen. Nevertheless, aberrant glycogen accumulation in neurons is a hallmark of patients suffering from Lafora disease or other polyglucosan disorders. Although these diseases are associated with mutations in genes involved in glycogen metabolism, the role of glycogen accumulation remains elusive. Here, we generated mouse and fly models expressing an active form of GS to force neuronal accumulation of glycogen. We present evidence that the progressive accumulation of glycogen in mouse and Drosophila neurons leads to neuronal loss, locomotion defects and reduced lifespan. Our results highlight glycogen accumulation in neurons as a direct cause of neurodegeneration.

Topics: Animals; Disease Models, Animal; Drosophila; Glycogen; Glycogen Storage Disease; Glycogen Synthase; Locomotion; Longevity; Mice; Neurodegenerative Diseases; Neurons

Lafora disease (progressive myoclonus epilepsy of Lafora type) is an autosomal recessive neurodegenerative disorder resulting from defects in the EPM2A gene. EPM2A encodes a 331-amino acid protein containing a carboxyl-terminal phosphatase catalytic domain. We demonstrate that the EPM2A gene product also contains an amino-terminal carbohydrate binding domain (CBD) and that the CBD is critical for association with glycogen both in vitro and in vivo. The CBD domain localizes the phosphatase to specific subcellular compartments that correspond to the expression pattern of glycogen processing enzyme, glycogen synthase. Mutations in the CBD result in mis-localization of the phosphatase and thereby suggest that the CBD targets laforin to intracellular glycogen particles where it is likely to function. Thus naturally occurring mutations within the CBD of laforin likely result in progressive myoclonus epilepsy due to mis-localization of phosphatase expression.

Topics: Amino Acid Sequence; Animals; Blotting, Western; Catalytic Domain; Cell Line; COS Cells; Cytoplasm; DNA, Complementary; Gene Library; Glycogen; Humans; Lafora Disease; Microscopy, Fluorescence; Models, Molecular; Molecular Sequence Data; Muscles; Mutation; Myoclonic Epilepsies, Progressive; Neurodegenerative Diseases; Phosphoric Monoester Hydrolases; Plasmids; Precipitin Tests; Protein Structure, Tertiary; Protein Tyrosine Phosphatases; Protein Tyrosine Phosphatases, Non-Receptor; Recombinant Proteins; Tissue Distribution; Transfection

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, the activity of which is inhibited by a variety of extracellular stimuli including insulin, growth factors, cell specification factors and cell adhesion. Consequently, inhibition of GSK-3 activity has been proposed to play a role in the regulation of numerous signalling pathways that elicit pleiotropic cellular responses. This report describes the identification and characterisation of potent and selective small molecule inhibitors of GSK-3.. SB-216763 and SB-415286 are structurally distinct maleimides that inhibit GSK-3alpha in vitro, with K(i)s of 9 nM and 31 nM respectively, in an ATP competitive manner. These compounds inhibited GSK-3beta with similar potency. However, neither compound significantly inhibited any member of a panel of 24 other protein kinases. Furthermore, treatment of cells with either compound stimulated responses characteristic of extracellular stimuli that are known to inhibit GSK-3 activity. Thus, SB-216763 and SB-415286 stimulated glycogen synthesis in human liver cells and induced expression of a beta-catenin-LEF/TCF regulated reporter gene in HEK293 cells. In both cases, compound treatment was demonstrated to inhibit cellular GSK-3 activity as assessed by activation of glycogen synthase, which is a direct target of this kinase.. SB-216763 and SB-415286 are novel, potent and selective cell permeable inhibitors of GSK-3. Therefore, these compounds represent valuable pharmacological tools with which the role of GSK-3 in cellular signalling can be further elucidated. Furthermore, development of similar compounds may be of use therapeutically in disease states associated with elevated GSK-3 activity such as non-insulin dependent diabetes mellitus and neurodegenerative disease.

Topics: Adenosine Triphosphate; Aminophenols; beta Catenin; Binding, Competitive; Calcium-Calmodulin-Dependent Protein Kinases; Cell Line; Cytoskeletal Proteins; Diabetes Mellitus, Type 2; Enzyme Activation; Gene Expression Regulation; Genes, Reporter; Glycogen; Glycogen Synthase; Glycogen Synthase Kinase 3; Glycogen Synthase Kinases; Humans; Indoles; Kinetics; Liver; Maleimides; Molecular Structure; Neurodegenerative Diseases; Protein Kinases; Recombinant Proteins; Signal Transduction; Trans-Activators; Transcription, Genetic