bims-meglyc Biomed News
on Metabolic disorders affecting glycosylation
Issue of 2022–12–18
43 papers selected by
Silvia Radenkovic, Frontiers in Congenital Disorders of Glycosylation Consortium
  1. Intracellular Citrate/Acetyl-CoA Flux and Endoplasmic Reticulum Acetylation: Connectivity is the Answer.
  2. Structural basis for matriglycan synthesis by the LARGE1 dual glycosyltransferase.
  3. A perspective on Drosophila genetics and its insight into human neurodegenerative disease.
  4. Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker.
  5. Glutathione Depletion and MicroRNA Dysregulation in Multiple System Atrophy: A Review.
  6. An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases.
  7. CRISPR: a tool with potential for genomic reprogramming in neurological disorders.
  8. Role of the Intermediate Filament Protein Peripherin in Health and Disease.
  9. "Tickle me pink": update in eosinophilic gastrointestinal disorders.
  10. The role of Notch signaling pathway in metabolic bone diseases.
  11. Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases.
  12. Brain modulation by the gut microbiota: from disease to therapy.
  13. Extracellular Matrix and Synapse Formation.
  14. More than meets the eye: The role of microglia in healthy and diseased retina.
  15. Phosphorylation of DGK.
  16. Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?
  17. Glycan-Based Electrochemical Biosensors: Promising Tools for the Detection of Infectious Diseases and Cancer Biomarkers.
  18. Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.
  19. Hemostatic Abnormalities in Gaucher Disease: Mechanisms and Clinical Implications.
  20. The Role of Oxidative Stress in Atherosclerosis.
  21. Strategies for activity analysis of single nucleotide polymorphisms associated with human diseases.
  22. Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases.
  23. Membrane Contact Sites in Autophagy.
  24. Deletion of POMT2 in Zebrafish Causes Degeneration of Photoreceptors.
  25. Construction of mouse cochlin mutants with different GAG-binding specificities and their use for immunohistochemistry.
  26. Brain borders at the central stage of neuroimmunology.
  27. N-Linked Glycosylation in Chinese Hamster Ovary Cells Is Critical for Insulin-like Growth Factor 1 Signaling.
  28. Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity.
  29. Glycosphingolipids in Diabetes, Oxidative Stress, and Cardiovascular Disease: Prevention in Experimental Animal Models.
  30. Targeting Mitochondrial Dynamics Proteins for the Development of Therapies for Cardiovascular Diseases.
  31. The genetic background of Parkinson's disease and novel therapeutic targets.
  32. Cellular functional, protective or damaging responses associated with different redox imbalance intensities: a comprehensive review.
  33. Identification and Characterization of GRASP55 O-GlcNAcylation.
  34. The Role of Ketogenic Diet in the Treatment of Neurological Diseases.
  35. Proteomics in Inherited Metabolic Disorders.
  36. Type 2 Diabetes Mellitus and Alzheimer's Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets.
  37. Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.
  38. Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases.
  39. Recent advances in computational algorithms and software for large-scale glycoproteomics.
  40. Extracellular vesicles in neurodegenerative diseases: A systematic review.
  41. Common mechanisms in pediatric acute liver failure.
  42. Promising novel therapeutic targets for kidney disease: emphasis on kidney-specific proteins.
  43. Emerging role for branched-chain amino acids metabolism in fibrosis.
  1. Mol Metab. 2022 Dec 10. pii: S2212-8778(22)00222-8. [Epub ahead of print] 101653
    Intracellular Citrate/Acetyl-CoA Flux and Endoplasmic Reticulum Acetylation: Connectivity is the Answer.
    Gonzalo Fernandez-Fuente, Michael J Rigby, Luigi Puglielli.
       BACKGROUND: Key cellular metabolites reflecting the immediate activity of metabolic enzymes as well as the functional metabolic state of intracellular organelles can act as powerful signal regulators to ensure the activation of homeostatic responses. The citrate/acetyl-CoA pathway, initially recognized for its role in intermediate metabolism, has emerged as a fundamental branch of this nutrient-sensing homeostatic response. Emerging studies indicate that fluctuations in acetyl-CoA availability within different cellular organelles and compartments provides substrate-level regulation of many biological functions. A fundamental aspect of these regulatory functions involves Nε-lysine acetylation.
    SCOPE OF REVIEW: Here, we will examine the emerging regulatory functions of the citrate/acetyl-CoA pathway and the specific role of the endoplasmic reticulum (ER) acetylation machinery in the maintenance of intracellular crosstalk and homeostasis. These functions will be analyzed in the context of associated human diseases and specific mouse models of dysfunctional ER acetylation and citrate/acetyl-CoA flux. A primary objective of this review is to highlight the complex yet integrated response of compartment- and organelle-specific Nε-lysine acetylation to the intracellular availability and flux of acetyl-CoA, linking this important post-translational modification to cellular metabolism.
    MAJOR CONCLUSIONS: The ER acetylation machinery regulates the proteostatic functions of the organelle as well as metabolic crosstalk between different intracellular organelles and compartments. This crosstalk enables the cell to impart adaptive responses within the ER and the secretory pathway. However, it also enables the ER to impart adaptive responses within different cellular organelles and compartments. Defects in the homeostatic balance of acetyl-CoA flux and ER acetylation reflect different but converging disease states in humans as well as converging phenotypes in relevant mouse models. In conclusion, citrate and acetyl-CoA should not only be seen as metabolic substrates of intermediate metabolism but also as signaling molecules that direct functional adaptation of the cell to both intracellular and extracellular messages. Future discoveries in CoA biology and acetylation are likely to yield novel therapeutic approaches.
    Keywords:  Acetyl-CoA; Acetylation; Citrate; CoA; Endoplasmic Reticulum
    DOI:  https://doi.org/10.1016/j.molmet.2022.101653
  2. PLoS One. 2022 ;17(12): e0278713
    Structural basis for matriglycan synthesis by the LARGE1 dual glycosyltransferase.
    Michael Katz, Ron Diskin.
      LARGE1 is a bifunctional glycosyltransferase responsible for generating a long linear polysaccharide termed matriglycan that links the cytoskeleton and the extracellular matrix and is required for proper muscle function. This matriglycan polymer is made with an alternating pattern of xylose and glucuronic acid monomers. Mutations in the LARGE1 gene have been shown to cause life-threatening dystroglycanopathies through the inhibition of matriglycan synthesis. Despite its major role in muscle maintenance, the structure of the LARGE1 enzyme and how it assembles in the Golgi are unknown. Here we present the structure of LARGE1, obtained by a combination of X-ray crystallography and single-particle cryo-EM. We found that LARGE1 homo-dimerizes in a configuration that is dictated by its coiled-coil stem domain. The structure shows that this enzyme has two canonical GT-A folds within each of its catalytic domains. In the context of its dimeric structure, the two types of catalytic domains are brought into close proximity from opposing monomers to allow efficient shuttling of the substrates between the two domains. Together, with putative retention of matriglycan by electrostatic interactions, this dimeric organization offers a possible mechanism for the ability of LARGE1 to synthesize long matriglycan chains. The structural information further reveals the mechanisms in which disease-causing mutations disrupt the activity of LARGE1. Collectively, these data shed light on how matriglycan is synthesized alongside the functional significance of glycosyltransferase oligomerization.
    DOI:  https://doi.org/10.1371/journal.pone.0278713
  3. Front Mol Biosci. 2022 ;9 1060796
    A perspective on Drosophila genetics and its insight into human neurodegenerative disease.
    Nancy M Bonini.
      Drosophila has been long appreciated as a classic genetic system for its ability to define gene function in vivo. Within the last several decades, the fly has also emerged as a premiere system for modeling and defining mechanisms of human disease by expressing dominant human disease genes and analyzing the effects. Here I discuss key aspects of this latter approach that first intrigued me to focus my laboratory research on this idea. Differences between the loss-of-function vs. the gain-of-function approach are raised-and the insight of these approaches for appreciating mechanisms that contribute to human neurodegenerative disease. The application of modifier genetics, which is a prominent goal of models of human disease, has implications for how specific genes or pathways intersect with the dominant disease-associated mechanisms. Models of human disease will continue to reveal unanticipated insight into fundamental cellular processes-insight that might be harder to glean from classical genetic methodologies vs modifier genetics of disease.
    Keywords:  Drosophila; chaperones; disease models; genetic screens; modifier genetics
    DOI:  https://doi.org/10.3389/fmolb.2022.1060796
  4. Int J Mol Sci. 2022 Dec 02. pii: 15166. [Epub ahead of print]23(23):
    Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker.
    Jun Feng, Zhaowei Chen, Wei Liang, Zhongping Wei, Guohua Ding.
      The kidney is a mitochondria-rich organ, and kidney diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal mitochondrial function. Mitochondrial dysfunction caused by mtDNA damage, including impaired mtDNA replication, mtDNA mutation, mtDNA leakage, and mtDNA methylation, is involved in the progression of kidney diseases. Herein, we review the roles of mtDNA damage in different setting of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). In a variety of kidney diseases, mtDNA damage is closely associated with loss of kidney function. The level of mtDNA in peripheral serum and urine also reflects the status of kidney injury. Alleviating mtDNA damage can promote the recovery of mitochondrial function by exogenous drug treatment and thus reduce kidney injury. In short, we conclude that mtDNA damage may serve as a novel biomarker for assessing kidney injury in different causes of renal dysfunction, which provides a new theoretical basis for mtDNA-targeted intervention as a therapeutic option for kidney diseases.
    Keywords:  kidney diseases; mitochondrial DNA; mtDNA leakage; mtDNA methylation; mtDNA mutation; mtDNA replication
    DOI:  https://doi.org/10.3390/ijms232315166
  5. Int J Mol Sci. 2022 Dec 01. pii: 15076. [Epub ahead of print]23(23):
    Glutathione Depletion and MicroRNA Dysregulation in Multiple System Atrophy: A Review.
    Chisato Kinoshita, Noriko Kubota, Koji Aoyama.
      Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by parkinsonism, cerebellar impairment, and autonomic failure. Although the causes of MSA onset and progression remain uncertain, its pathogenesis may involve oxidative stress via the generation of excess reactive oxygen species and/or destruction of the antioxidant system. One of the most powerful antioxidants is glutathione, which plays essential roles as an antioxidant enzyme cofactor, cysteine-storage molecule, major redox buffer, and neuromodulator, in addition to being a key antioxidant in the central nervous system. Glutathione levels are known to be reduced in neurodegenerative diseases. In addition, genes regulating redox states have been shown to be post-transcriptionally modified by microRNA (miRNA), one of the most important types of non-coding RNA. miRNAs have been reported to be dysregulated in several diseases, including MSA. In this review, we focused on the relation between glutathione deficiency, miRNA dysregulation and oxidative stress and their close relation with MSA pathology.
    Keywords:  glutathione; microRNA; multiple system atrophy; neurodegenerative disease; oxidative stress; α-synuclein
    DOI:  https://doi.org/10.3390/ijms232315076
  6. Front Neurosci. 2022 ;16 1030512
    An update on the therapeutic implications of long-chain acyl-coenzyme A synthetases in nervous system diseases.
    Zhimin Wu, Jun Sun, Zhi Liao, Jia Qiao, Chuan Chen, Cong Ling, Hui Wang.
      Long-chain acyl-coenzyme A synthetases (ACSLs) are a family of CoA synthetases that activate fatty acid (FA) with chain lengths of 12-20 carbon atoms by forming the acyl-AMP derivative in an isozyme-specific manner. This family mainly includes five members (ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6), which are thought to have specific and different functions in FA metabolism and oxidative stress of mammals. Accumulating evidence shows that the dysfunction of ACSLs is likely to affect cell proliferation and lead to metabolic diseases in multiple organs and systems through different signaling pathways and molecular mechanisms. Hence, a central theme of this review is to emphasize the therapeutic implications of ACSLs in nervous system disorders.
    Keywords:  fatty acid (FA) metabolism; ferroptosis; long-chain acyl-coenzyme A synthetases (ACSLs); nervous system diseases; targeted therapy
    DOI:  https://doi.org/10.3389/fnins.2022.1030512
  7. Mol Biol Rep. 2022 Dec 12.
    CRISPR: a tool with potential for genomic reprogramming in neurological disorders.
    Yogesh K Dhuriya, Aijaz A Naik.
      The intricate neural circuitry of the brain necessitates precise and synchronized transcriptional programs. Any disturbance during embryonic or adult development, whether caused by genetic or environmental factors, may result in refractory and recurrent neurological disorders. Inadequate knowledge of the pathogenic mechanisms underlying neurological disorders is the primary obstacle to the development of effective treatments, necessitating the development of alternative therapeutic approaches to identify rational molecular targets. Recently, with the evolution of CRISPR-Cas9 technology, an engineered RNA system provides precise and highly effective correction or silencing of disease-causing mutations by modulating expression and thereby avoiding the limitations of the RNA interference strategy. This article discusses the CRISPR-Cas9 technology, its mechanisms, and the limitations of the new technology. We provide a glimpse of how the far-reaching implications of CRISPR can open new avenues for the development of tools to combat neurological disorders, as well as a review of recent attempts by neuroscientists to launch therapeutic correction.
    Keywords:  Brain; CRISPR; Gene therapy; Neurological diseases; sgRNA
    DOI:  https://doi.org/10.1007/s11033-022-08136-z
  8. Int J Mol Sci. 2022 Dec 06. pii: 15416. [Epub ahead of print]23(23):
    Role of the Intermediate Filament Protein Peripherin in Health and Disease.
    Roberta Romano, Victoria Stefania Del Fiore, Cecilia Bucci.
      Intermediate filaments are the most heterogeneous class among cytoskeletal elements. While some of them have been well-characterized, little is known about peripherin. Peripherin is a class III intermediate filament protein with a specific expression in the peripheral nervous system. Epigenetic modifications are involved in this cell-type-specific expression. Peripherin has important roles in neurite outgrowth and stability, axonal transport, and axonal myelination. Moreover, peripherin interacts with proteins involved in vesicular trafficking, signal transduction, DNA/RNA processing, protein folding, and mitochondrial metabolism, suggesting a role in all these processes. This review collects information regarding peripherin gene regulation, post-translational modifications, and functions and its involvement in the onset of a number of diseases.
    Keywords:  Charcot–Marie–Tooth disease; amyotrophic lateral sclerosis; diabetes; intermediate filaments; neurodegeneration; neurodegenerative diseases; neurons; peripheral nervous system; peripherin
    DOI:  https://doi.org/10.3390/ijms232315416
  9. Curr Opin Gastroenterol. 2023 Jan 01. 39(1): 36-42
    "Tickle me pink": update in eosinophilic gastrointestinal disorders.
    Angela Y Lam, Nirmala Gonsalves.
       PURPOSE OF REVIEW: Eosinophilic gastrointestinal diseases (EGIDs) outside of the esophagus have been previously enigmatic and rare diagnoses. Fortunately, increasing research over the past few decades has led to an improved understanding of disease pathophysiology and epidemiology. This has been foundational for developing accurate nomenclature, diagnostic criteria, and therapeutics.
    RECENT FINDINGS: This article will review recent updates in nonesophageal EGIDs. Accurate disease classification and nomenclature developed from international consensus are now available, as well as data challenging the notion that abnormal endoscopic findings are rare in this population. Studies on natural history, outcomes, and impact on patient quality of life are reviewed. Lastly, retrospective studies and clinical trials on EGID therapies are summarized.
    SUMMARY: With a standardized nomenclature system for EGIDs now established, formal diagnostic guidelines and criteria for nonesophageal EGIDs are in active development. While management remains challenging compared with eosinophilic esophagitis, research and development of effective, steroid-sparing therapies (primarily through biologics and dietary therapy) remain underway. In eosinophilic colitis, the rarest EGID, research remains focused on illuminating pathophysiology. Ongoing research will continue to improve understanding of natural history, outcomes, and therapeutic options for these diseases.
    DOI:  https://doi.org/10.1097/MOG.0000000000000896
  10. Biochem Pharmacol. 2022 Dec 10. pii: S0006-2952(22)00472-5. [Epub ahead of print]207 115377
    The role of Notch signaling pathway in metabolic bone diseases.
    Yongguang Gao, Zhanda Fu, Junxia Guan, Xinhua Liu, Qing Zhang.
      Metabolic bone diseases is the third most common endocrine diseases after diabetes and thyroid diseases. More than 500 million people worldwide suffer from metabolic bone diseases. The generation and development of bone metabolic diseases is a complex process regulated by multiple signaling pathways, among which the Notch signaling pathway is one of the most important pathways. The Notch signaling pathway regulates the differentiation and function of osteoblasts and osteoclasts, and affects the process of cartilage formation, bone formation and bone resorption. Genetic mutations in upstream and downstream of Notch signaling genes can lead to a series of metabolic bone diseases, such as Alagille syndrome, Adams-Oliver syndrome and spondylocostal dysostosis. In this review, we analyzed the mechanisms of Notch ligands, Notch receptors and signaling molecules in the process of signal transduction, and summarized the progress on the pathogenesis and clinical manifestations of bone metabolic diseases caused by Notch gene mutation. We hope to draw attention to the role of the Notch signaling pathway in metabolic bone diseases and provide new ideas and approaches for the diagnosis and treatment of metabolic bone diseases.
    Keywords:  Metabolic bone diseases; Notch receptor; Notch signaling pathway; Osteoblast; Osteoclast; Spondylocostal dysostosis
    DOI:  https://doi.org/10.1016/j.bcp.2022.115377
  11. Int J Mol Sci. 2022 Dec 01. pii: 15109. [Epub ahead of print]23(23):
    Natural-Product-Mediated Autophagy in the Treatment of Various Liver Diseases.
    Guifang Fan, Fanghong Li, Ping Wang, Xuejing Jin, Runping Liu.
      Autophagy is essential for the maintenance of hepatic homeostasis, and autophagic malfunction has been linked to the pathogenesis of substantial liver diseases. As a popular source of drug discovery, natural products have been used for centuries to effectively prevent the progression of various liver diseases. Emerging evidence has suggested that autophagy regulation is a critical mechanism underlying the therapeutic effects of these natural products. In this review, relevant studies are retrieved from scientific databases published between 2011 and 2022, and a novel scoring system was established to critically evaluate the completeness and scientific significance of the reviewed literature. We observed that numerous natural products were suggested to regulate autophagic flux. Depending on the therapeutic or pathogenic role autophagy plays in different liver diseases, autophagy-regulative natural products exhibit different therapeutic effects. According to our novel scoring system, in a considerable amount of the involved studies, convincing and reasonable evidence to elucidate the regulatory effects and underlying mechanisms of natural-product-mediated autophagy regulation was missing and needed further illustration. We highlight that autophagy-regulative natural products are valuable drug candidates with promising prospects for the treatment of liver diseases and deserve more attention in the future.
    Keywords:  autophagy; liver diseases; natural products; pharmacodynamics; scoring system
    DOI:  https://doi.org/10.3390/ijms232315109
  12. J Adv Res. 2022 Dec 07. pii: S2090-1232(22)00267-3. [Epub ahead of print]
    Brain modulation by the gut microbiota: from disease to therapy.
    Sarmistha Mitra, Raju Dash, Amena Al Nishan, Sarmin Ummey Habiba, Il Soo Moon.
       BACKGROUND: The gut microbiota (GM) and brain are strongly associated, which significantly affects neuronal development and disorders. GM-derived metabolites modulate neuronal function and influence many cascades in age-related neurodegenerative disorders (NDDs). Because of the dual role of GM in neuroprotection and neurodegeneration, understanding the balance between beneficial and harmful bacteria is crucial for applying this approach to clinical therapies.
    AIM: of the review This review briefly discusses the role of the gut-brain relationship in promoting brain and cognitive function. Although a healthy gut environment is helpful for brain function, gut dysbiosis can disrupt the brain's environment and create a vicious cycle of degenerative cascades. The ways in which the GM population can affect brain function and the development of neurodegeneration are also discussed. In the treatment and management of NDDs, the beneficial effects of methods targeting GM populations and their derivatives, including probiotics, prebiotics, and fecal microbial transplantation (FMT) are also highlighted. Key scientific concept of the review In this review, we aimed to provide a deeper understanding of the mechanisms of the gut microbe-brain relationship and their twin roles in neurodegeneration progression and therapeutic applications. Here, we attempted to highlight the different pathways connecting the brain and gut, together with the role of GM in neuroprotection and neuronal development. Furthermore, potential roles of GM metabolites in the pathogenesis of brain disorders and in strategies for its treatment are also investigated. By analyzing existing in vitro and clinical studies, this review attempts to identify new and promising therapeutic strategies for central nervous system (CNS) disorders. As the connection between the gut microbe-brain relationship and responses to NDD treatments is less studied, this review will provide new insights into the global mechanisms of GM modulation in disease progression, and identify potential future perspectives for developing new therapies to treat NDDs.
    Keywords:  Gut microbiota; Neurodegeneration; Neurogenesis; Neuroprotection
    DOI:  https://doi.org/10.1016/j.jare.2022.12.001
  13. Biosci Rep. 2022 Dec 12. pii: BSR20212411. [Epub ahead of print]
    Extracellular Matrix and Synapse Formation.
    Lei Yang, Mengping Wei, Biyu Xing, Chen Zhang.
      The extracellular matrix (ECM) is a complex molecular network distributed throughout the extracellular space of different tissues as well as the neuronal system. Previous studies have identified various ECM components that play important roles in neuronal maturation and signal transduction. ECM components are reported to be involved in neurogenesis, neuronal migration, and axonal growth by interacting or binding to specific receptors. In addition, the ECM is found to regulate synapse formation, the stability of the synaptic structure, and synaptic plasticity. Here, we mainly reviewed the effects of various ECM components on synapse formation and briefly described the related diseases caused by the abnormality of several ECM components.
    Keywords:  Synapse formation; extracellular matrix; neuroscience; synaptic plasticity; synaptogenesis
    DOI:  https://doi.org/10.1042/BSR20212411
  14. Front Immunol. 2022 ;13 1006897
    More than meets the eye: The role of microglia in healthy and diseased retina.
    Elisa Murenu, Maximilian-Joachim Gerhardt, Martin Biel, Stylianos Michalakis.
      Microglia are the main resident immune cells of the nervous system and as such they are involved in multiple roles ranging from tissue homeostasis to response to insults and circuit refinement. While most knowledge about microglia comes from brain studies, some mechanisms have been confirmed for microglia cells in the retina, the light-sensing compartment of the eye responsible for initial processing of visual information. However, several key pieces of this puzzle are still unaccounted for, as the characterization of retinal microglia has long been hindered by the reduced population size within the retina as well as the previous lack of technologies enabling single-cell analyses. Accumulating evidence indicates that the same cell type may harbor a high degree of transcriptional, morphological and functional differences depending on its location within the central nervous system. Thus, studying the roles and signatures adopted specifically by microglia in the retina has become increasingly important. Here, we review the current understanding of retinal microglia cells in physiology and in disease, with particular emphasis on newly discovered mechanisms and future research directions.
    Keywords:  disease; homeostasis; immune system; microglia; retina
    DOI:  https://doi.org/10.3389/fimmu.2022.1006897
  15. Adv Biol Regul. 2022 Dec 07. pii: S2212-4926(22)00081-1. [Epub ahead of print]88 100941
    Phosphorylation of DGK.
    Xin Barbernitz, Daniel M Raben.
      Diacylglycerol (DAG) and phosphatidic acid (PtdOH) play important roles in a variety of signaling cascades (Carrasco and Merida, 2007; Stace and Ktistakis, 2006). Therefore, the physiological roles and regulatory mechanisms controlling the levels of these lipids are important. One class of enzymes capable of coordinating the levels of these two lipids are the diacylglycerol kinases (DGKs). DGKs catalyze the transfer of the γ-phosphate of ATP to the hydroxyl group of DAG which generates PtdOH(Merida et al., 2008; Sakane et al., 2007). As DGKs reciprocally modulate the relative levels of these two signaling lipids, it is not surprising that there is increasing interest in understanding the mechanism underlying the catalysis and regulation of these kinases. While post-translational modifications (PTMs) are often involved in enzyme regulation, there is surprisingly little information regarding the PTMs on these enzymes and their roles in modulating their activity and function. In this review, we will summarize what is known about one PTM on DGKs, phosphorylation, and the possible functions of this modification.
    DOI:  https://doi.org/10.1016/j.jbior.2022.100941
  16. Int J Mol Sci. 2022 Nov 30. pii: 14989. [Epub ahead of print]23(23):
    Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?
    Luana Toniolo, Giuseppe Sirago, Nicola Fiotti, Emiliana Giacomello.
      A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC's form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC's form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies.
    Keywords:  Golgi Complex; Limb girdle muscular dystrophy; dystrophin associated protein complex; early secretory pathway; glycosylation; muscular dystrophy
    DOI:  https://doi.org/10.3390/ijms232314989
  17. Molecules. 2022 Dec 03. pii: 8533. [Epub ahead of print]27(23):
    Glycan-Based Electrochemical Biosensors: Promising Tools for the Detection of Infectious Diseases and Cancer Biomarkers.
    Danilo Echeverri, Jahir Orozco.
      Glycan-based electrochemical biosensors are emerging as analytical tools for determining multiple molecular targets relevant to diagnosing infectious diseases and detecting cancer biomarkers. These biosensors allow for the detection of target analytes at ultra-low concentrations, which is mandatory for early disease diagnosis. Nanostructure-decorated platforms have been demonstrated to enhance the analytical performance of electrochemical biosensors. In addition, glycans anchored to electrode platforms as bioreceptors exhibit high specificity toward biomarker detection. Both attributes offer a synergy that allows ultrasensitive detection of molecular targets of clinical interest. In this context, we review recent advances in electrochemical glycobiosensors for detecting infectious diseases and cancer biomarkers focused on colorectal cancer. We also describe general aspects of structural glycobiology, definitions, and classification of electrochemical biosensors and discuss relevant works on electrochemical glycobiosensors in the last ten years. Finally, we summarize the advances in electrochemical glycobiosensors and comment on some challenges and limitations needed to advance toward real clinical applications of these devices.
    Keywords:  cancer biomarker; electrochemical glycobiosensor; glycan; infectious disease
    DOI:  https://doi.org/10.3390/molecules27238533
  18. Int J Mol Sci. 2022 Dec 04. pii: 15296. [Epub ahead of print]23(23):
    Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.
    Ting-Wan Kao, Yao-Chen Chuang, Hsin-Lun Lee, Chia-Chun Kuo, Yao-An Shen.
      Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks. These building blocks are mostly utilized in the synthesis of macromolecules and antioxidants for redox homeostasis. A recent study revealed the cellular and molecular interconnections between glutamine and cancer stemness in the cell. Researchers have increasingly focused on glutamine catabolism in their attempt to discover an effective therapy for cancer stem cells. Targeting catalytic enzymes in glutaminolysis, such as glutaminase (GLS), is achievable with small molecule inhibitors, some of which are in early-phase clinical trials and have promising safety profiles. This review summarizes the current findings in glutaminolysis of CSCs and focuses on novel cancer therapies that target glutaminolysis in CSCs.
    Keywords:  cancer stem cells; glutaminase; glutaminolysis; metabolic compensation; therapeutic resistance
    DOI:  https://doi.org/10.3390/ijms232315296
  19. J Clin Med. 2022 Nov 24. pii: 6920. [Epub ahead of print]11(23):
    Hemostatic Abnormalities in Gaucher Disease: Mechanisms and Clinical Implications.
    Silvia Linari, Giancarlo Castaman.
      Gaucher disease (GD) is a rare inherited lysosomal metabolism disorder, characterized by an accumulation into lysosomes of reticuloendothelial cells, especially in the bone marrow, spleen, and liver of β-glucosylceramide and glucosyl sphingosine, which is its deacylated product. Impaired storage is responsible for a chronic inflammatory state at the sites of accumulation and together represents the pathophysiological cause of GD. GD is a progressive, multi-organ chronic disorder. Type 1 GD is the most prevalent form, with heterogeneous multisystem involvement and different severity of symptoms at any age. Hematological involvement is consistent, and a bleeding tendency is frequent, particularly at diagnosis. Several coagulation and primary hemostasis abnormalities are observed in GD. Bleeding manifestations are rarely severe and usually mucocutaneous. Post-operative, delivery, and post-partum hemorrhages are also common. Thrombocytopenia, platelet function defects, and clotting abnormalities, alone or variably associated, contribute to increase the risk of bleeding in GD. Enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) are the two specific available treatments effective in improving typical hematological symptoms and abnormalities, including those of hemostasis. However, the use of medication to potentiate hemostasis may be also useful in defined clinical situations: recent starting of ERT/SRT, surgery, delivery, and life-threatening bleeding.
    Keywords:  Gaucher disease; bleeding; clotting factors; hemostasis; platelets
    DOI:  https://doi.org/10.3390/jcm11236920
  20. Cells. 2022 Nov 30. pii: 3843. [Epub ahead of print]11(23):
    The Role of Oxidative Stress in Atherosclerosis.
    Matthew Batty, Martin R Bennett, Emma Yu.
      Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.
    Keywords:  atherosclerosis; mitochondria; oxidative stress
    DOI:  https://doi.org/10.3390/cells11233843
  21. Clin Genet. 2022 Dec 17.
    Strategies for activity analysis of single nucleotide polymorphisms associated with human diseases.
    Naixia Ren, Shangkun Dai, Shumin Ma, Fengtang Yang.
      Genome-Wide Association Studies (GWAS) have identified a large number of single nucleotide polymorphism (SNP) sites associated with human diseases. In the annotation of human diseases, especially cancers, SNPs, as an important component of genetic factors, have gained increasing attention. Given that most of the SNPs are located in non-coding regions, the functional verification of these SNPs is a great challenge. The key to functional annotation for risk SNPs is to screen SNPs with regulatory activity from thousands of disease associated-SNPs. In this review, we systematically recapitulate the characteristics and functional roles of SNP sites, discuss three parallel reporter screening strategies in detail based on barcode tag classification, and recommend the common in silico strategies to help supplement the annotation of SNP sites with epigenetic activity analysis, prediction of target genes and trans-acting factors. We hope that this review will contribute to this exuberant research field by providing robust activity analysis strategies that can facilitate the translation of GWAS results into personalized diagnosis and prevention measures for human diseases. This article is protected by copyright. All rights reserved.
    Keywords:  GWAS; SNPs; activity analysis; human diseases; personalized medicine
    DOI:  https://doi.org/10.1111/cge.14282
  22. Int J Mol Sci. 2022 Dec 04. pii: 15288. [Epub ahead of print]23(23):
    Mitochondrial Dysfunction and Oxidative Stress in Hereditary Ectopic Calcification Diseases.
    Lukas L Nollet, Olivier M Vanakker.
      Ectopic calcification (EC) is characterized by an abnormal deposition of calcium phosphate crystals in soft tissues such as blood vessels, skin, and brain parenchyma. EC contributes to significant morbidity and mortality and is considered a major health problem for which no effective treatments currently exist. In recent years, growing emphasis has been placed on the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of EC. Impaired mitochondrial respiration and increased levels of reactive oxygen species can be directly linked to key molecular pathways involved in EC such as adenosine triphosphate homeostasis, DNA damage signaling, and apoptosis. While EC is mainly encountered in common diseases such as diabetes mellitus and chronic kidney disease, studies in rare hereditary EC disorders such as pseudoxanthoma elasticum or Hutchinson-Gilford progeria syndrome have been instrumental in identifying the precise etiopathogenetic mechanisms leading to EC. In this narrative review, we describe the current state of the art regarding the role of mitochondrial dysfunction and oxidative stress in hereditary EC diseases. In-depth knowledge of aberrant mitochondrial metabolism and its local and systemic consequences will benefit the research into novel therapies for both rare and common EC disorders.
    Keywords:  Hutchinson–Gilford progeria syndrome; central nervous system calcification; ectopic calcification; mitochondria; oxidative stress; pseudoxanthoma elasticum; rare diseases
    DOI:  https://doi.org/10.3390/ijms232315288
  23. Cells. 2022 Nov 28. pii: 3813. [Epub ahead of print]11(23):
    Membrane Contact Sites in Autophagy.
    Emma Zwilling, Fulvio Reggiori.
      Eukaryotes utilize different communication strategies to coordinate processes between different cellular compartments either indirectly, through vesicular transport, or directly, via membrane contact sites (MCSs). MCSs have been implicated in lipid metabolism, calcium signaling and the regulation of organelle biogenesis in various cell types. Several studies have shown that MCSs play a crucial role in the regulation of macroautophagy, an intracellular catabolic transport route that is characterized by the delivery of cargoes (proteins, protein complexes or aggregates, organelles and pathogens) to yeast and plant vacuoles or mammalian lysosomes, for their degradation and recycling into basic metabolites. Macroautophagy is characterized by the de novo formation of double-membrane vesicles called autophagosomes, and their biogenesis requires an enormous amount of lipids. MCSs appear to have a central role in this supply, as well as in the organization of the autophagy-related (ATG) machinery. In this review, we will summarize the evidence for the participation of specific MCSs in autophagosome formation, with a focus on the budding yeast and mammalian systems.
    Keywords:  MAMs; autophagosome; endoplasmic reticulum; lipid droplets; lipid transfer; mitochondria; phagophore; plasma membrane; vacuole
    DOI:  https://doi.org/10.3390/cells11233813
  24. Int J Mol Sci. 2022 Nov 26. pii: 14809. [Epub ahead of print]23(23):
    Deletion of POMT2 in Zebrafish Causes Degeneration of Photoreceptors.
    Yu Liu, Jaclyn M Rittershaus, Miao Yu, Rachel Sager, Huaiyu Hu.
      Mutations in the extracellular matrix protein eyes shut homolog (EYS) are a common cause of retinitis pigmentosa, a blinding disease characterized by photoreceptor degeneration. EYS binds to matriglycan, a carbohydrate modification on O-mannosyl glycan substitutions of the cell-surface glycoprotein α-dystroglycan. Patients with mutations in enzymes required for the biosynthesis of matriglycan exhibit syndromic retinal atrophy, along with brain malformations and congenital muscular dystrophy. Protein O-mannosyltransferase 2 (POMT2) is an enzyme required for the synthesis of O-mannosyl glycans. To evaluate the roles of O-mannosyl glycans in photoreceptor health, we generated protein O-mannosyltransferase 2 (pomt2) mutant zebrafish by CRISPR. pomt2 mutation resulted in a loss of matriglycan and abolished binding of EYS protein to α-dystroglycan. Mutant zebrafish presented with hydrocephalus and hypoplasia of the cerebellum, as well as muscular dystrophy. EYS protein was enriched near photoreceptor connecting cilia in the wild-type, but its presence and proper localization was significantly reduced in mutant animals. The mutant retina exhibited mis-localization of opsins and increased apoptosis in both rod and cone photoreceptors. Immunofluorescence intensity of G protein subunit alpha transducin 2 (GNAT2) antibody (a general cone marker) and 1D4 antibody (a long double cone marker) in mutant retinas did not differ from wild-type retinas at 1-month post fertilization, but was reduced at 6 months post fertilization, indicating significant cone degeneration. These data suggest that POMT2-mediated O-mannosyl glycosylation is required for EYS protein localization to the connecting cilium region and photoreceptor survival.
    Keywords:  congenital muscular dystrophy; inherited retinal degeneration; photoreceptor degeneration; retina; retinitis pigmentosa; zebrafish
    DOI:  https://doi.org/10.3390/ijms232314809
  25. Biochem J. 2022 Dec 13. pii: BCJ20220339. [Epub ahead of print]
    Construction of mouse cochlin mutants with different GAG-binding specificities and their use for immunohistochemistry.
    Kazuo Yamamoto, Karin Murakami, Ryo Tamura, Sanae Ikehara, Hayato Ota, Tomomi Ichimiya, Naoki Matsumoto, Hisahiro Matsubara, Shoko Nishihara, Yuzuru Ikehara.
      Glycosaminoglycan (GAG) is a polysaccharide present on the cell surface as an extracellular matrix component, and is composed of repeating disaccharide units consisting of an amino sugar and uronic acid except in the case of the keratan sulfate. Sulfated GAGs, such as heparan sulfate, heparin, and chondroitin sulfate mediate signal transduction of growth factors, and their functions vary with the type and degree of sulfated modification. We have previously identified human and mouse cochlins as proteins that bind to sulfated GAGs. Here, we prepared a recombinant cochlin fused to human IgG-Fc or Protein A at the C-terminus as a detection and purification tag and investigated the ligand specificity of cochlin. We found that cochlin can be used as a specific probe for highly sulfated heparan sulfate and chondroitin sulfate E. We then used mutant analysis to identify the mechanism by which cochlin recognizes GAGs and developed a GAG detection system using cochlin. Interestingly, a mutant lacking the vWA2 domain bound to various types of GAGs. The N-terminal amino acid residues of cochlin contributed to its binding to heparin. Pathological specimens from human myocarditis patients were stained with a cochlin-Fc mutant. The results showed that both tryptase-positive and tryptase-negative mast cells were stained with this mutant. The identification of detailed modification patterns of GAGs is an important method to elucidate the molecular mechanisms of various diseases. The method developed for evaluating the expression of highly sulfated GAGs will help understand the biological and pathological importance of sulfated GAGs in the future.
    Keywords:  biotechnology; glycobiology; glycosaminoglycans; pathology
    DOI:  https://doi.org/10.1042/BCJ20220339
  26. Nature. 2022 Dec;612(7940): 417-429
    Brain borders at the central stage of neuroimmunology.
    Justin Rustenhoven, Jonathan Kipnis.
      The concept of immune privilege suggests that the central nervous system is isolated from the immune system. However, recent studies have highlighted the borders of the central nervous system as central sites of neuro-immune interactions. Although the nervous and immune systems both function to maintain homeostasis, under rare circumstances, they can develop pathological interactions that lead to neurological or psychiatric diseases. Here we discuss recent findings that dissect the key anatomical, cellular and molecular mechanisms that enable neuro-immune responses at the borders of the brain and spinal cord and the implications of these interactions for diseases of the central nervous system.
    DOI:  https://doi.org/10.1038/s41586-022-05474-7
  27. Int J Mol Sci. 2022 Nov 29. pii: 14952. [Epub ahead of print]23(23):
    N-Linked Glycosylation in Chinese Hamster Ovary Cells Is Critical for Insulin-like Growth Factor 1 Signaling.
    Rupashree Salvi, Chandan Kumar, Krupanshi Brahmbhatt, Rambhadur Subedi, Susan Idicula-Thomas, Taruna Madan, Barnali Biswas.
      Cell surface proteins carrying N-glycans play important roles in inter- and intracellular processes including cell adhesion, development, and cellular recognition. Dysregulation of the glycosylation machinery has been implicated in various diseases, and investigation of global differential cell surface proteome effects due to the loss of N-glycosylation will provide comprehensive insights into their pathogenesis. Cell surface proteins isolated from Parent Pro-5 CHO cells (W5 cells), two CHO mutants with loss of N-glycosylation function derived from Pro-5 CHO (Lec1 and Lec4 cells), were subjected to proteome analysis via high-resolution LCMS. We identified 44 and 43 differentially expressed membrane proteins in Lec1 and Lec4 cells, respectively, as compared to W5 cells. The defective N-glycosylation mutants showed increased abundance of integrin subunits in Lec1 and Lec4 cells at the cell surface. We also found significantly reduced levels of IGF-1R (Insulin like growth factor-1 receptor); a receptor tyrosine kinase; and the GTPase activating protein IQGAP1 (IQ motif-containing GTPase activating protein), a highly conserved cytoplasmic scaffold protein) in Lec1 and Lec4 cells. In silico docking studies showed that the IQ domain of IQGAP1 interacts with the kinase domain of IGF-1R. The integrin signaling and insulin growth factor receptor signaling were also enriched according to GSEA analysis and pathway analysis of differentially expressed proteins. Significant reductions of phosphorylation of ERK1 and ERK2 in Lec1 and Lec4 cells were observed upon IGF-1R ligand (IGF-1 LR3) stimulation. IGF-1 LR3, known as Long arginine3-IGF-1, is a synthetic protein and lengthened analog of insulin-like growth factor 1. The work suggests a novel mechanism for the activation of IGF-1 dependent ERK signaling in CHO cells, wherein IQGAP1 plausibly functions as an IGF-1R-associated scaffold protein. Appropriate glycosylation by the enzymes MGAT1 and MGAT5 is thus essential for processing of cell surface receptor IGF-1R, a potential binding partner in IQGAP1 and ERK signaling, the integral components of the IGF pathway.
    Keywords:  MAP kinases (MAPKs); N-glycosylation; Orbitrap Mass Spectrometry (MS); Ras GTPase activating Protein (IQGAP1); insulin-like growth factor 1 receptor; integrins; protein phosphorylation; receptor tyrosine kinase
    DOI:  https://doi.org/10.3390/ijms232314952
  28. Cancers (Basel). 2022 Nov 26. pii: 5840. [Epub ahead of print]14(23):
    Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity.
    Jianmei Huang, Jianming Huang, Guonan Zhang.
      Sialylation is an enzymatic process that covalently attaches sialic acids to glycoproteins and glycolipids and terminates them by creating sialic acid-containing glycans (sialoglycans). Sialoglycans, usually located in the outmost layers of cells, play crucial biological roles, notably in tumor transformation, growth, metastasis, and immune evasion. Thus, a deeper comprehension of sialylation in cancer will help to facilitate the development of innovative cancer therapies. Cancer sialylation-related articles have consistently increased over the last four years. The primary subjects of these studies are sialylation, cancer, immunotherapy, and metastasis. Tumor cells activate endothelial cells and metastasize to distant organs in part by the interactions of abnormally sialylated integrins with selectins. Furthermore, cancer sialylation masks tumor antigenic epitopes and induces an immunosuppressive environment, allowing cancer cells to escape immune monitoring. Cytotoxic T lymphocytes develop different recognition epitopes for glycosylated and nonglycosylated peptides. Therefore, targeting tumor-derived sialoglycans is a promising approach to cancer treatments for limiting the dissemination of tumor cells, revealing immunogenic tumor antigens, and boosting anti-cancer immunity. Exploring the exact tumor sialoglycans may facilitate the identification of new glycan targets, paving the way for the development of customized cancer treatments.
    Keywords:  anti-tumor therapy; cancer; immunotherapy; metastasis; sialic acid; sialylation
    DOI:  https://doi.org/10.3390/cancers14235840
  29. Int J Mol Sci. 2022 Dec 06. pii: 15442. [Epub ahead of print]23(23):
    Glycosphingolipids in Diabetes, Oxidative Stress, and Cardiovascular Disease: Prevention in Experimental Animal Models.
    Amrita Balram, Spriha Thapa, Subroto Chatterjee.
      Diabetes contributes to about 30% morbidity and mortality world-wide and has tidal wave increases in several countries in Asia. Diabetes is a multi-factorial disease compounded by inflammation, dyslipidemia, atherosclerosis, and is sometimes accompanied with gains in body weight. Sphingolipid pathways that interplay in the enhancement of the pathology of this disease may be potential therapeutic targets. Thus, the application of advanced sphingolipidomics may help predict the progression of this disease and therapeutic outcomes in man. Pre-clinical studies using various experimental animal models of diabetes provide valuable information on the role of sphingolipid signaling networks in diabetes and the efficacy of drugs to determine the translatability of innovative discoveries to man. In this review, we discuss three major concepts regarding sphingolipids and diabetes. First, we discuss a possible involvement of a monosialodihexosylceramide (GM3) in insulin-insulin receptor interactions. Second, a potential role for ceramide (Cer) and lactosylceramide (LacCer) in apoptosis and mitochondrial dysfunction is proposed. Third, a larger role of LacCer in antioxidant status and inflammation is discussed. We also discuss how inhibitors of glycosphingolipid synthesis can ameliorate diabetes in experimental animal models.
    Keywords:  diabetes; inflammation; insulin; lipidomics; sphingolipids
    DOI:  https://doi.org/10.3390/ijms232315442
  30. Int J Mol Sci. 2022 Nov 25. pii: 14741. [Epub ahead of print]23(23):
    Targeting Mitochondrial Dynamics Proteins for the Development of Therapies for Cardiovascular Diseases.
    Alexander V Blagov, Sergey Kozlov, Tatiana Blokhina, Vasily N Sukhorukov, Aleksander N Orekhov.
      Cardiovascular diseases are one of the leading causes of death worldwide. The identification of new pathogenetic targets contributes to more efficient development of new types of drugs for the treatment of cardiovascular diseases. This review highlights the problem of mitochondrial dynamics disorders, in the context of cardiovascular diseases. A change in the normal function of mitochondrial dynamics proteins is one of the reasons for the development of the pathological state of cardiomyocytes. Based on this, therapeutic targeting of these proteins may be a promising strategy in the development of cardiac drugs. Here we will consider changes for each process of mitochondrial dynamics in cardiovascular diseases: fission and fusion of mitochondria, mitophagy, mitochondrial transport and biogenesis, and also analyze the prospects of the considered protein targets based on existing drug developments.
    Keywords:  cardiovascular disease; mitochondria; mitochondrial dynamic
    DOI:  https://doi.org/10.3390/ijms232314741
  31. Expert Opin Ther Targets. 2022 Dec 16. 1-10
    The genetic background of Parkinson's disease and novel therapeutic targets.
    András Salamon, Dénes Zádori, László Szpisjak, Péter Klivényi, László Vécsei.
       INTRODUCTION: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The median age of disease onset is around 60 years. From a genetic point of view, PD is basically considered a sporadic, idiopathic disease, however, hereditary components can be detected in 5-10% of patients. Expanding data are available regarding the targeted molecular therapy of the disease.
    AREAS COVERED: The aim of this current review article is to provide brief clinical and molecular insight into three important genetic forms (LRRK2, SNCA, GBA) of hereditary PD subtypes and to present the human clinical trials in relation to these forms of the disease.
    EXPERT OPINION: These small hereditary subgroups are crucially important in drug development, because the general trend is that clinical trials that treat PD patients as a large group, without any separation, do not meet expectations. As a result, no long term conclusions can currently be drawn regarding the effectiveness of the molecules tested in these phase 1 and 2 studies. Further precise studies are needed in the near future.
    Keywords:  GBA; LRRK2; Parkinson’s disease; SNCA; genetic
    DOI:  https://doi.org/10.1080/14728222.2022.2153037
  32. Curr Med Chem. 2022 Dec 09.
    Cellular functional, protective or damaging responses associated with different redox imbalance intensities: a comprehensive review.
    Andrea Del Campo, Rodrigo Valenzuela, Luis A Videla, Jessica Zúñiga-Hernandez.
       BACKGROUND: Reactive species (RS) are produced in aerobic and anaerobic cells at different concentrations and exposure times, which may trigger diverse responses depending on the cellular antioxidant potential and defensive devices.
    METHODS: Study searches were carried out using the PubMed database of the National Library of Medicine-National Institutes of Health.
    RESULTS: Cellular RS include reactive oxygen (ROS), nitrogen (RNS), lipid (RLS) and electrophilic species that determine either cell homeostasis or dysfunctional biomolecules. The complexity of redox signalling is associated with the variety of RS produced, the reactivity of the target biomolecules with RS, the multiplicity of the counteracting processes available, and the exposure time. The continuous distortion in the pro-oxidant/antioxidant balance favoring the former is defined as oxidative stress, whose intensity determines (i) the basal not harmful unbalance (oxidative eustress) at RS levels in the pM to nM range that supports physiological processes (e.g., immune function, thyroid function, insulin action) and beneficial responses to external interventions via redox signalling; or (ii) the excessive, toxic distortion (oxidative distress) at RS levels exceeding those in the oxidative eustress zone, leading to the unspecific oxidation of biomolecules and loss of their functions causing cell death with associated pathological states.
    CONCLUSION: The cellular redox imbalance is a complex phenomenon whose underlying mechanisms are beginning to be understood, although how RS initiates cell signalling is a matter of debate. Knowledge of this aspect will provide a better understanding of how RS triggers the pathogenesis and progression of the disease and uncover future therapeutic measures.
    Keywords:  Beneficial responses; Disease; Oxidative distress; Oxidative eustress; Physiological functions; Redox imbalance
    DOI:  https://doi.org/10.2174/0929867330666221209093343
  33. Methods Mol Biol. 2023 ;2557 743-753
    Identification and Characterization of GRASP55 O-GlcNAcylation.
    Xiaoyan Zhang.
      O-GlcNAcylation is a posttranslational modification of proteins that adds a single sugar, β-N-acetylglucosamine (GlcNAc), to Ser/Thr residues. Extensive studies have been conducted to identify and characterize substrates of this modification but mostly focused on cytosolic and nuclear proteins. This chapter describes a detailed protocol used to determine the O-GlcNAcylation of GRASP55, the first O-GlcNAcylated Golgi protein identified, including how its O-GlcNAcylation level responds to glucose deprivation. In addition, this chapter also provides a detailed method to express and purify O-GlcNAcylated GRASP55 in bacteria for further in vitro functional assays. This protocol could be applied to other Golgi proteins that are potentially O-GlcNAcylated.
    Keywords:  GRASP55; Glucose deprivation; Golgi apparatus; O-GlcNAcylation; OGA; OGT; Phosphorylation; Purification
    DOI:  https://doi.org/10.1007/978-1-0716-2639-9_44
  34. Nutrients. 2022 Nov 24. pii: 5003. [Epub ahead of print]14(23):
    The Role of Ketogenic Diet in the Treatment of Neurological Diseases.
    Damian Dyńka, Katarzyna Kowalcze, Agnieszka Paziewska.
      Over a hundred years of study on the favourable effect of ketogenic diets in the treatment of epilepsy have contributed to a long-lasting discussion on its potential influence on other neurological diseases. A significant increase in the number of scientific studies in that field has been currently observed. The aim of this paper is a widespread, thorough analysis of the available scientific evidence in respect of the role of the ketogenic diet in the therapy of neurological diseases such as: epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and migraine. A wide range of the mechanisms of action of the ketogenic diet has been demonstrated in neurological diseases, including, among other effects, its influence on the reduction in inflammatory conditions and the amount of reactive oxygen species (ROS), the restoration of the myelin sheath of the neurons, the formation and regeneration of mitochondria, neuronal metabolism, the provision of an alternative source of energy for neurons (ketone bodies), the reduction in glucose and insulin concentrations, the reduction in amyloid plaques, the induction of autophagy, the alleviation of microglia activation, the reduction in excessive neuronal activation, the modulation of intestinal microbiota, the expression of genes, dopamine production and the increase in glutamine conversion into GABA. The studies discussed (including randomised controlled studies), conducted in neurological patients, have stressed the effectiveness of the ketogenic diet in the treatment of epilepsy and have demonstrated its promising therapeutic potential in Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and migraine. A frequent advantage of the diet was demonstrated over non-ketogenic diets (in the control groups) in the therapy of neurological diseases, with simultaneous safety and feasibility when conducting the nutritional model.
    Keywords:  Alzheimer’s disease (AD); Parkinson’s disease (PD); anti-inflammatory; brain; epilepsy; high fat; inflammatory; ketogenic; ketogenic diet; ketone bodies; low carb; migraine; multiple sclerosis (MS); neuroinflammation; neurological diseases; neurone; neuroplasticity; neurotransmitters; nutrition; prevention; treatment
    DOI:  https://doi.org/10.3390/nu14235003
  35. Int J Mol Sci. 2022 Nov 25. pii: 14744. [Epub ahead of print]23(23):
    Proteomics in Inherited Metabolic Disorders.
    Maria Del Pilar Chantada-Vázquez, Susana B Bravo, Sofía Barbosa-Gouveia, José V Alvarez, María L Couce.
      Inherited metabolic disorders (IMD) are rare medical conditions caused by genetic defects that interfere with the body's metabolism. The clinical phenotype is highly variable and can present at any age, although it more often manifests in childhood. The number of treatable IMDs has increased in recent years, making early diagnosis and a better understanding of the natural history of the disease more important than ever. In this review, we discuss the main challenges faced in applying proteomics to the study of IMDs, and the key advances achieved in this field using tandem mass spectrometry (MS/MS). This technology enables the analysis of large numbers of proteins in different body fluids (serum, plasma, urine, saliva, tears) with a single analysis of each sample, and can even be applied to dried samples. MS/MS has thus emerged as the tool of choice for proteome characterization and has provided new insights into many diseases and biological systems. In the last 10 years, sequential window acquisition of all theoretical fragmentation spectra mass spectrometry (SWATH-MS) has emerged as an accurate, high-resolution technique for the identification and quantification of proteins differentially expressed between healthy controls and IMD patients. Proteomics is a particularly promising approach to help obtain more information on rare genetic diseases, including identification of biomarkers to aid early diagnosis and better understanding of the underlying pathophysiology to guide the development of new therapies. Here, we summarize new and emerging proteomic technologies and discuss current uses and limitations of this approach to identify and quantify proteins. Moreover, we describe the use of proteomics to identify the mechanisms regulating complex IMD phenotypes; an area of research essential to better understand these rare disorders and many other human diseases.
    Keywords:  biomarkers; enzyme replacement therapy; inborn errors of metabolism; lysosomal disorders; proteomics
    DOI:  https://doi.org/10.3390/ijms232314744
  36. Int J Mol Sci. 2022 Dec 04. pii: 15287. [Epub ahead of print]23(23):
    Type 2 Diabetes Mellitus and Alzheimer's Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets.
    Rim Hamzé, Etienne Delangre, Stefania Tolu, Manon Moreau, Nathalie Janel, Danielle Bailbé, Jamileh Movassat.
      The global prevalence of diabetes mellitus and Alzheimer's disease is increasing alarmingly with the aging of the population. Numerous epidemiological data suggest that there is a strong association between type 2 diabetes and an increased risk of dementia. These diseases are both degenerative and progressive and share common risk factors. The amyloid cascade plays a key role in the pathophysiology of Alzheimer's disease. The accumulation of amyloid beta peptides gradually leads to the hyperphosphorylation of tau proteins, which then form neurofibrillary tangles, resulting in neurodegeneration and cerebral atrophy. In Alzheimer's disease, apart from these processes, the alteration of glucose metabolism and insulin signaling in the brain seems to induce early neuronal loss and the impairment of synaptic plasticity, years before the clinical manifestation of the disease. The large amount of evidence on the existence of insulin resistance in the brain during Alzheimer's disease has led to the description of this disease as "type 3 diabetes". Available animal models have been valuable in the understanding of the relationships between type 2 diabetes and Alzheimer's disease, but to date, the mechanistical links are poorly understood. In this non-exhaustive review, we describe the main molecular mechanisms that may link these two diseases, with an emphasis on impaired insulin and IGF-1 signaling. We also focus on GSK3β and DYRK1A, markers of Alzheimer's disease, which are also closely associated with pancreatic β-cell dysfunction and type 2 diabetes, and thus may represent common therapeutic targets for both diseases.
    Keywords:  Alzheimer’s disease; Aβ peptide; DYRK1A; diabetes; glycogen synthase kinase 3; insulin deficiency; insulin resistance; insulin secretion; tau
    DOI:  https://doi.org/10.3390/ijms232315287
  37. Int J Mol Sci. 2022 Dec 03. pii: 15271. [Epub ahead of print]23(23):
    Blood-Brain Barrier Disruption and Its Involvement in Neurodevelopmental and Neurodegenerative Disorders.
    Ana Aragón-González, Pamela J Shaw, Laura Ferraiuolo.
      The blood-brain barrier (BBB) is a highly specialized and dynamic compartment which regulates the uptake of molecules and solutes from the blood. The relevance of the maintenance of a healthy BBB underpinning disease prevention as well as the main pathomechanisms affecting BBB function will be detailed in this review. Barrier disruption is a common aspect in both neurodegenerative diseases, such as amyotrophic lateral sclerosis, and neurodevelopmental diseases, including autism spectrum disorders. Throughout this review, conditions altering the BBB during the earliest and latest stages of life will be discussed, revealing common factors involved. Due to the barrier's role in protecting the brain from exogenous components and xenobiotics, drug delivery across the BBB is challenging. Potential therapies based on the BBB properties as molecular Trojan horses, among others, will be reviewed, as well as innovative treatments such as stem cell therapies. Additionally, due to the microbiome influence on the normal function of the brain, microflora modulation strategies will be discussed. Finally, future research directions are highlighted to address the current gaps in the literature, emphasizing the idea that common therapies for both neurodevelopmental and neurodegenerative pathologies exist.
    Keywords:  blood–brain barrier; neurodegeneration; neurodevelopment; therapies
    DOI:  https://doi.org/10.3390/ijms232315271
  38. Transl Neurodegener. 2022 Dec 12. 11(1): 53
    Extracellular vesicles, from the pathogenesis to the therapy of neurodegenerative diseases.
    Xiaohuan Xia, Yi Wang, Jialin C Zheng.
      Extracellular vesicles (EVs) are small bilipid layer-enclosed vesicles that can be secreted by all tested types of brain cells. Being a key intercellular communicator, EVs have emerged as a key contributor to the pathogenesis of various neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease through delivery of bioactive cargos within the central nervous system (CNS). Importantly, CNS cell-derived EVs can be purified via immunoprecipitation, and EV cargos with altered levels have been identified as potential biomarkers for the diagnosis and prognosis of NDs. Given the essential impact of EVs on the pathogenesis of NDs, pathological EVs have been considered as therapeutic targets and EVs with therapeutic effects have been utilized as potential therapeutic agents or drug delivery platforms for the treatment of NDs. In this review, we focus on recent research progress on the pathological roles of EVs released from CNS cells in the pathogenesis of NDs, summarize findings that identify CNS-derived EV cargos as potential biomarkers to diagnose NDs, and comprehensively discuss promising potential of EVs as therapeutic targets, agents, and drug delivery systems in treating NDs, together with current concerns and challenges for basic research and clinical applications of EVs regarding NDs.
    Keywords:  Biomarker; Exosome; Extracellular vesicle; Neurodegenerative disease; Therapeutics
    DOI:  https://doi.org/10.1186/s40035-022-00330-0
  39. Curr Opin Chem Biol. 2022 Dec 14. pii: S1367-5931(22)00123-5. [Epub ahead of print]72 102238
    Recent advances in computational algorithms and software for large-scale glycoproteomics.
    Daniel A Polasky, Alexey I Nesvizhskii.
      Glycoproteomics, or characterizing glycosylation events at a proteome scale, has seen rapid advances in methods for analyzing glycopeptides by tandem mass spectrometry in recent years. These advances have enabled acquisition of far more comprehensive and large-scale datasets, precipitating an urgent need for improved informatics methods to analyze the resulting data. A new generation of glycoproteomics search methods has recently emerged, using glycan fragmentation to split the identification of a glycopeptide into peptide and glycan components and solve each component separately. In this review, we discuss these new methods and their implications for large-scale glycoproteomics, as well as several outstanding challenges in glycoproteomics data analysis, including validation of glycan assignments and quantitation. Finally, we provide an outlook on the future of glycoproteomics from an informatics perspective, noting the key challenges to achieving widespread and reproducible glycopeptide annotation and quantitation.
    Keywords:  Database Search; False Discovery Rate; Glycopeptide Identification; Glycoproteomics; Software
    DOI:  https://doi.org/10.1016/j.cbpa.2022.102238
  40. Front Mol Neurosci. 2022 ;15 1061076
    Extracellular vesicles in neurodegenerative diseases: A systematic review.
    Alok Raghav, Manish Singh, Goo-Bo Jeong, Richa Giri, Saurabh Agarwal, Sanjay Kala, Kirti Amresh Gautam.
       Introduction: Extracellular vesicles (EVs) are known to have a significant role in the central nervous system (CNS) and neurodegenerative disease.
    Methods: PubMed, Scopus, ISI Web of Science, EMBASE, and Google Scholar were used to identify published articles about EV modifications (2012 to Feb 2022).
    Results: In total, 1,435 published papers were identified among the searched articles, with 1,128 non-duplicate publications being identified. Following the screening of titles and abstracts, 214 publications were excluded; following the full-text screening of 93 published articles, another 33 publications were excluded. The remaining 60 studies were considered. The kappa statistic of 0.868 indicated that the raters were highly reliable. Furthermore, the inter-reliability and intra-reliability coefficients were found to be 0.931 and 0.908, respectively, indicating strong reliability and consistency between the eligible studies identified by the raters. A total of 27 relevant studies demonstrated the role of EVs as therapeutic and diagnostic biomarkers in neurodegenerative diseases. Of note, 19 and 14 studies, respectively, found EVs to be pioneering in diagnostic and therapeutic roles.
    Discussion: EVs play an important role in the central nervous system (CNS), aiding in cell-to-cell communication and serving as a diagnostic marker and therapeutic target in a variety of neurodegenerative diseases. EVs are the home of several proteins [including-synuclein (-syn) and tau proteins], lipids, and genetic materials such as DNA and RNA. The presence of novel miRNAs in EVs suggests biomarkers for the diagnosis and screening of neurodegenerative disorders. Furthermore, EVs play an important role in the pathogenesis of such disorders. This systematic review discussed the current state of EVs' role in neurological diseases, as well as some preclinical studies on the therapeutic and diagnostic potential of EVs.
    Keywords:  biomarker; extracellular vesicles; neurodegenerative disease; neurological disease; therapeutics
    DOI:  https://doi.org/10.3389/fnmol.2022.1061076
  41. Trends Mol Med. 2022 Dec 07. pii: S1471-4914(22)00299-4. [Epub ahead of print]
    Common mechanisms in pediatric acute liver failure.
    Jake P Mann, Dominic Lenz, Zania Stamataki, Deirdre Kelly.
      Acute liver failure (ALF) is a rare but potentially fatal disease in children. The etiology is multifactorial, including infection, autoimmune, and genetic disorders, as well as indeterminate hepatitis, which has a higher requirement for liver transplantation. Activation of the innate and adaptive immune systems leads to hepatocyte-specific injury which is mitigated by T regulatory cell activation. Recovery of the native liver depends on activation of apoptotic and regenerative pathways, including the integrated stress response (ISR; e.g., PERK), p53, and HNF4α. Loss-of-function mutations in these pathways cause recurrent ALF in response to non-hepatotropic viruses. Deeper understanding of these mechanisms will lead to improved diagnosis, management, and outcomes for pediatric ALF.
    Keywords:  acute liver failure; adenovirus; hepatocyte regeneration; integrated stress response
    DOI:  https://doi.org/10.1016/j.molmed.2022.11.006
  42. Drug Discov Today. 2022 Dec 09. pii: S1359-6446(22)00459-7. [Epub ahead of print] 103466
    Promising novel therapeutic targets for kidney disease: emphasis on kidney-specific proteins.
    Tathambika Tejeswini Sen, Ajinath Kale, Maciej Lech, Hans-Joachim Anders, Anil Bhanudas Gaikwad.
      Worldwide, around 850 million people are diagnosed with kidney disease but the available treatment options are still limited. Preclinical studies propose a plethora of druggable targets that can attenuate kidney disease and could qualify as novel therapeutic strategies, although most of these targets still await clinical testing. Here, we review some promising candidate targets for chronic kidney disease (CKD): intermedin (IMD), periostin, sirtuin (SIRT), the cannabinoid receptor, Klotho, and uromodulin. For acute kidney injury (AKI), we discuss Apelin, Elabela (ELA), growth differentiation factor (GDF)-15, Fyn kinase, and Klotho. Target selection for further clinical development should consider redundancies with the standard of care, potential synergistic effects with existing treatments, as well as the potential of additional effects on the cardiovascular system as a common comorbidity in patients with kidney disease. Teaser: Understanding how novel therapeutic targets are involved in kidney disease pathophysiology will motivate researchers to investigate these targets in clinical settings to validate their therapeutic potential.
    Keywords:  Klotho; acute kidney injury; chronic kidney diseases; existing therapies; intermedin; novel therapeutic targets
    DOI:  https://doi.org/10.1016/j.drudis.2022.103466
  43. Pharmacol Res. 2022 Dec 09. pii: S1043-6618(22)00550-3. [Epub ahead of print]187 106604
    Emerging role for branched-chain amino acids metabolism in fibrosis.
    Tiangang Wu, Mengling Wang, Fengling Ning, Shilin Zhou, Xuetao Hu, Hong Xin, Svetlana Reilly, Xuemei Zhang.
      Fibrosis is a common pathological feature of organ diseases resulting from excessive production of extracellular matrix, which accounts for significant morbidity and mortality. However, there is currently no effective treatment targeting fibrogenesis. Recently, metabolic alterations are increasingly considered as essential factors underlying fibrogenesis, and especially research on metabolic regulation of amino acids is flourishing. Among them, branched-chain amino acids (BCAAs) are the most abundant essential amino acids, including leucine, isoleucine and valine, which play significant roles in the substance and energy metabolism and their regulation. Dysregulation of BCAAs metabolism has been proven to contribute to numerous diseases. In this review, we summarize the metabolic regulation of fibrosis and the changes in BCAAs metabolism secondary to fibrosis. We also review the effects and mechanisms of the BCAAs intervention, and its therapeutic targeting in hepatic, renal and cardiac fibrosis, with a focus on the fibrosis in liver and associated hepatocellular carcinoma.
    Keywords:  Branched-chain amino acids; Fibrosis; Liver; Metabolism
    DOI:  https://doi.org/10.1016/j.phrs.2022.106604
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