GNE deficiency impairs Myogenesis in C2C12 cells and cannot be rescued by ManNAc supplementation.

GNE myopathy (GNEM) is a late-onset muscle atrophy, caused by mutations in the gene for the key enzyme of sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE). With an incidence of one to nine cases per million it is an ultra-rare, so far untreatable, autosomal recessive disease. Several attempts have been made to treat GNEM patients by oral supplementation with sialic acid precursors (e.

Evaluation of -Acetylmannosamine Administration to Restore Sialylation in -Deficient Human Embryonal Kidney Cells.

Background: A key mechanism in the neuromuscular disease GNE myopathy (GNEM) is believed to be that point mutations in the gene impair sialic acid synthesis - maybe due to UDP--acetylglucosamine 2-epimerase/-acetylmannosamine kinase (GNE) activity restrictions - and resulting in muscle tissue loss. -acetylmannosamine (ManNAc) is the first product of the bifunctional GNE enzyme and can therefore be regarded as a precursor of sialic acids. This study investigates whether this is also a suitable substance for restoring the sialic acid content in -deficient cells.

Glycation Interferes with the Activity of the Bi-Functional UDP--Acetylglucosamine 2-Epimerase/-Acetyl-mannosamine Kinase (GNE).

Mutations in the gene coding for the bi-functional UDP--acetylglucosamine 2-epimerase/-acetylmannosamine kinase (GNE), the key enzyme of the sialic acid biosynthesis, are responsible for autosomal-recessive GNE myopathy (GNEM). GNEM is an adult-onset disease with a yet unknown exact pathophysiology. Since the protein appears to work adequately for a certain period of time even though the mutation is already present, other effects appear to influence the onset and progression of the disease.

Disturbance of Key Cellular Subproteomes upon Propofol Treatment Is Associated with Increased Permeability of the Blood-Brain Barrier.

Background: Propofol is a short-acting anesthetic, which is often used for induction and maintenance of general anesthesia, sedation for mechanically ventilated adults and procedural sedation. Several side effects of propofol are known and a substantial number of patients suffer from post-operative delirium after propofol application. In this study, we analyzed the effect of propofol on the function and protein expression profile on a proteome-wide scale.

Glycation Interferes with the Expression of Sialyltransferases in Meningiomas.

Meningiomas are the most common non-malignant intracranial tumors and prefer, like most tumors, anaerobic glycolysis for energy production (Warburg effect). This anaerobic glycolysis leads to an increased synthesis of the metabolite methylglyoxal (MGO) or glyoxal (GO), which is known to react with amino groups of proteins. This reaction is called glycation, thereby building advanced glycation end products (AGEs).

Glycation of benign meningioma cells leads to increased invasion.

Meningiomas are the most common non-malignant intracranial tumors. Like most tumors, meningiomas prefer anaerobic glycolysis for energy production (Warburg effect). This leads to an increased synthesis of the metabolite methylglyoxal (MGO).

Glycation Increases the Risk of Microbial Traversal through an Endothelial Model of the Human Blood-Brain Barrier after Use of Anesthetics.

The function of the human blood-brain barrier (BBB), consisting mainly of the basement membrane and microvascular endothelial cells, is to protect the brain and regulate its metabolism. Dysfunction of the BBB can lead to increased permeability, which can be linked with several pathologies, including meningitis, sepsis, and postoperative delirium. Advanced glycation end products (AGE) are non-enzymatic, posttranslational modifications of proteins, which can affect their function.

Sialylation of Human Natural Killer (NK) Cells is Regulated by IL-2.

Sialic acids are terminal sugars on the cell surface that are found on all cell types including immune cells like natural killer (NK) cells. The attachment of sialic acids to different glycan structures is catalyzed by sialyltransferases in the Golgi. However, the expression pattern of sialyltransferases in NK cells and their expression after activation has not yet been analyzed.

Glycation Leads to Increased Polysialylation and Promotes the Metastatic Potential of Neuroblastoma Cells.

Neuroblastoma is the second most frequent extracranial tumor, affecting young children worldwide. One hallmark of tumors such as neuroblastomas, is the expression of polysialic acid, which interferes with adhesion and may promote invasion and metastasis. Since tumor cells use glycolysis for energy production, they thereby produce as side product methylglyoxal (MGO), which reacts with proteins to advanced glycation end products in a mechanism called glycation.

Analyzing the Permeability of the Blood-Brain Barrier by Microbial Traversal through Microvascular Endothelial Cells.

The human blood-brain barrier (BBB) is characterized by a very low permeability for biomolecules in order to protect and regulate the metabolism of the brain. The BBB is mainly formed out of endothelial cells embedded in collagen IV and fibronectin-rich basement membranes. Several pathologies result from dysfunction of the BBB followed by microbial traversal, causing diseases such as meningitis.

Increased Expression of Immature Mannose-Containing Glycoproteins and Sialic Acid in Aged Mouse Brains.

Aging represents the accumulation of changes in an individual over time, encompassing physical, psychological, and social changes. Posttranslational modifications of proteins such as glycosylation, including sialylation or glycation, are proposed to be involved in this process, since they modulate a variety of molecular and cellular functions. In this study, we analyzed selected posttranslational modifications and the respective proteins on which they occur in young and old mouse brains.

Glycation of macrophages induces expression of pro-inflammatory cytokines and reduces phagocytic efficiency.

Glycation and the accumulation of advanced glycation end products (AGEs) are known to occur during normal aging but also in the progression of several diseases, such as diabetes. Diabetes type II and aging both lead to impaired wound healing. It has been demonstrated that macrophages play an important role in impaired wound healing, however, the underlying causes remain unknown.

Glycation interferes with natural killer cell function.

One hallmark of molecular aging is glycation, better known as formation of so-called advanced glycation end products (AGEs), where reactive carbonyls react with amino-groups of proteins. AGEs accumulate over time and are responsible for various age-dependent diseases and impairments. Two very potent dicarbonyls to generate AGEs are glyoxal (GO) and methylglyoxal (MGO).

Ascorbic acid leads to glycation and interferes with neurite outgrowth.

Ascorbic acid better known as vitamin C, is a reducing carbohydrate needed for a variety of functions in the human body. The most important characteristic of ascorbic acid is the ability to donate two electrons, predestining it as a major player in balancing the physiological redox state and as a necessary cofactor in multiple enzymatic hydroxylation processes. Ascorbic acid can be reversibly oxidized in two steps, leading to semidehydroascorbic acid and dehydroascorbic acid, respectively.

Advanced glycation endproducts and polysialylation affect the turnover of the neural cell adhesion molecule (NCAM) and the receptor for advanced glycation endproducts (RAGE).

The balance between protein synthesis and degradation regulates the amount of expressed proteins. This protein turnover is usually quantified as the protein half-life time. Several studies suggest that protein degradation decreases with age and leads to increased deposits of damaged and non-functional proteins.

The expression of sialyltransferases is regulated by the bioavailability and biosynthesis of sialic acids.

Glycosylation is the most frequent and important post-translational modification of proteins. It occurs on specific consensus sequences but the final structure of a particular glycan is not coded on the DNA, rather it depends on the expression of the required enzymes and the availability of substrates (activated monosaccharides). Sialic acid (Sia) is the terminal monosaccharide of most glycoproteins or glycolipids (= glycoconjugates) and involved in a variety of function on molecular (e.

Mutation of a putative MAP kinase consensus site regulates NCAM endocytosis and NCAM-dependent neurite outgrowth.

The cytoplasmic domain of the neural cell adhesion molecule NCAM contains several putative serine/threonine phosphorylation sites whose functions are largely unknown. Human NCAM140 (NCAM140) possesses a potential MAP kinase phosphorylation site at threonine (T) 803. The aim of this study was to analyze a possible phosphorylation of NCAM140 by MAP kinases and to identify the functional role of T803.

Increased Polysialylation of the Neural Cell Adhesion Molecule in a Transgenic Mouse Model of Sialuria.

Sialuria is a rare autosomal dominant disorder of mammalian metabolism, caused by defective feedback inhibition of the UDP-N-acetylglucosamine-2-epimerase N-acetylmannosamine kinase (GNE), the key enzyme of sialic acid biosynthesis. Sialuria is characterized by overproduction of free sialic acid in the cell cytoplasm. Patients exhibit vastly increased urinary excretion of sialic acid and show differently pronounced developmental delays.

Novel insights in the dysfunction of human blood-brain barrier after glycation.

The blood-brain barrier (BBB) provides a dynamic and complex interface consisting of endothelial cells, pericytes and astrocytes, which are embedded in a collagen and fibronectin-rich basement membrane. This complex structure restricts the diffusion of small hydrophilic solutes and macromolecules as well as the transmigration of leukocytes into the brain. It has been shown that carbonyl stress followed by the formation of advanced glycation endproducts (AGE=glycation) interfere with the BBB integrity and function.

Neuroprotective and neuroregenerative effects of nimodipine in a model system of neuronal differentiation and neurite outgrowth.

Nimodipine is a Ca2+-channel antagonist mainly used for the management of aneurysmal subarachnoid hemorrhage (aSAH) to prevent cerebral vasospasms. However, it is not clear if the better outcome of nimodipine-treated patients is mainly due to vasodilatation or whether other cellular neuroprotective or neuregenerative effects of nimodipine are involved. We analysed PC12 cells after different stress stimuli with or without nimodipine pretreatment.

Advanced glycation endproducts interfere with adhesion and neurite outgrowth.

Advanced glycation endproducts (AGEs) represent a non-enzymatic posttranslational protein modification. AGEs are generated by a series of chemical reactions of free reducing monosaccharides, such as glucose, fructose or metabolites of the monosaccharide metabolism with amino groups of proteins. After oxidation, dehydration and condensation, stable AGE-modifications are formed.

Investigation of the neuroprotective impact of nimodipine on Neuro2a cells by means of a surgery-like stress model.

Nimodipine is well characterized for the management of SAH (subarachnoid hemorrhage) and has been shown to promote a better outcome and less DIND (delayed ischemic neurological deficits). In rat experiments, enhanced axonal sprouting and higher survival of motoneurons was demonstrated after cutting or crushing the facial nerve by nimodipine. These results were confirmed in clinical trials following vestibular Schwannoma surgery.

ATP interferes with neural cell adhesion molecule-induced neurite outgrowth.

The neural cell adhesion molecule (NCAM) is a member of the immunoglobulin superfamily and involved in the development and regeneration of the nervous system. NCAM is expressed in three major isoforms. Two of them have large intracellular domains of different lengths and are named according to their apparent molecular weight as NCAM140 or NCAM180.