-
Advances in Carbohydrate Chemistry and... 2018Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their... (Review)
Review
Sialic acids are cytoprotectors, mainly localized on the surface of cell membranes with multiple and outstanding cell biological functions. The history of their structural analysis, occurrence, and functions is fascinating and described in this review. Reports from different researchers on apparently similar substances from a variety of biological materials led to the identification of a 9-carbon monosaccharide, which in 1957 was designated "sialic acid." The most frequently occurring member of the sialic acid family is N-acetylneuraminic acid, followed by N-glycolylneuraminic acid and O-acetylated derivatives, and up to now over about 80 neuraminic acid derivatives have been described. They appeared first in the animal kingdom, ranging from echinoderms up to higher animals, in many microorganisms, and are also expressed in insects, but are absent in higher plants. Sialic acids are masks and ligands and play as such dual roles in biology. Their involvement in immunology and tumor biology, as well as in hereditary diseases, cannot be underestimated. N-Glycolylneuraminic acid is very special, as this sugar cannot be expressed by humans, but is a xenoantigen with pathogenetic potential. Sialidases (neuraminidases), which liberate sialic acids from cellular compounds, had been known from very early on from studies with influenza viruses. Sialyltransferases, which are responsible for the sialylation of glycans and elongation of polysialic acids, are studied because of their significance in development and, for instance, in cancer. As more information about the functions in health and disease is acquired, the use of sialic acids in the treatment of diseases is also envisaged.
Topics: Animals; Carbohydrate Conformation; Humans; Lysosomal Storage Diseases; Mucolipidoses; N-Acetylneuraminic Acid; Neoplasms; Sialic Acid Storage Disease
PubMed: 30509400
DOI: 10.1016/bs.accb.2018.09.001 -
International Journal of Molecular... Sep 2020Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate -acetylglucosamine: lysosomal-enzyme--acetylglucosamine-1-phosphotransferase... (Review)
Review
Mucolipidosis II and III (ML II/III) are caused by a deficiency of uridine-diphosphate -acetylglucosamine: lysosomal-enzyme--acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase, EC2.7.8.17), which tags lysosomal enzymes with a mannose 6-phosphate (M6P) marker for transport to the lysosome. The process is performed by a sequential two-step process: first, GlcNAc-1-phosphotransferase catalyzes the transfer of GlcNAc-1-phosphate to the selected mannose residues on lysosomal enzymes in the cis-Golgi network. The second step removes GlcNAc from lysosomal enzymes by -acetylglucosamine-1-phosphodiester α--acetylglucosaminidase (uncovering enzyme) and exposes the mannose 6-phosphate (M6P) residues in the trans-Golgi network, in which the enzymes are targeted to the lysosomes by M6Preceptors. A deficiency of GlcNAc-1-phosphotransferase causes the hypersecretion of lysosomal enzymes out of cells, resulting in a shortage of multiple lysosomal enzymes within lysosomes. Due to a lack of GlcNAc-1-phosphotransferase, the accumulation of cholesterol, phospholipids, glycosaminoglycans (GAGs), and other undegraded substrates occurs in the lysosomes. Clinically, ML II and ML III exhibit quite similar manifestations to mucopolysaccharidoses (MPSs), including specific skeletal deformities known as dysostosis multiplex and gingival hyperplasia. The life expectancy is less than 10 years in the severe type, and there is no definitive treatment for this disease. In this review, we have described the updated diagnosis and therapy on ML II/III.
Topics: Animals; Biological Transport, Active; Disease Models, Animal; Enzyme Replacement Therapy; Genetic Therapy; Glycosaminoglycans; Hematopoietic Stem Cell Transplantation; Humans; Lysosomes; Mannosephosphates; Mucolipidoses
PubMed: 32957425
DOI: 10.3390/ijms21186812 -
Proceedings of the National Academy of... Aug 2020Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle...
Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria-lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria-lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria-lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria-lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria-lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria-lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.
Topics: Biological Transport; Calcium; Humans; Lysosomes; Mitochondria; Mitochondrial Dynamics; Mucolipidoses; Transient Receptor Potential Channels
PubMed: 32703809
DOI: 10.1073/pnas.2003236117 -
Acta Ophthalmologica Dec 2020In the era of precision medicine, genomic characterization of blind patients is critical. Here, we evaluate the effects of comprehensive genetic analysis on the...
PURPOSE
In the era of precision medicine, genomic characterization of blind patients is critical. Here, we evaluate the effects of comprehensive genetic analysis on the etiologic diagnosis of potentially hereditary vision loss and its impact on clinical management.
METHODS
We studied 100 non-syndromic and syndromic Spanish patients with a clinical diagnosis of blindness caused by alterations on the retina, choroid, vitreous and/or optic nerve. We used a next-generation sequencing (NGS) panel (OFTALMOgenics™), developed and validated within this study, including up to 362 genes previously associated with these conditions.
RESULTS
We identified the genetic cause of blindness in 45% of patients (45/100). A total of 28.9% of genetically diagnosed cases (13/45) were syndromic and, of those, in 30.8% (4/13) extraophthalmic features had been overlooked and/or not related to visual impairment before genetic testing, including cases with Mainzer-Saldino, Bardet-Biedl, mucolipidosis and MLCRD syndromes. In two additional cases-syndromic blindness had been proposed before, but not specifically diagnosed, and one patient with Heimler syndrome had been misdiagnosed as an Usher case before testing. 33.3% of the genetically diagnosed patients (15/45) had causative variants in genes targeted by clinical trials exploring the curative potential of gene therapy approaches.
CONCLUSION
Comprehensive genomic testing provided clinically relevant insights in a large proportion of blind patients, identifying potential therapeutic opportunities or previously undiagnosed syndromes in 42.2% of the genetically diagnosed cases (19/45).
Topics: Disease Management; Genetic Testing; Genomics; High-Throughput Nucleotide Sequencing; Humans; Optic Nerve Diseases; Pedigree; Phenotype; Retinal Diseases; Syndrome
PubMed: 32483926
DOI: 10.1111/aos.14479 -
International Journal of Biological... 2022Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a...
Diabetic cardiomyopathy (DCM) is associated with oxidative stress and augmented inflammation in the heart. Neuraminidases (NEU) 1 has initially been described as a lysosomal protein which plays a role in the catabolism of glycosylated proteins. We investigated the role of NEU1 in the myocardium in diabetic heart. Streptozotocin (STZ) was injected intraperitoneally to induce diabetes in mice. Neonatal rat ventricular myocytes (NRVMs) were used to verify the effect of shNEU1 . NEU1 is up-regulated in cardiomyocytes under diabetic conditions. NEU1 inhibition alleviated oxidative stress, inflammation and apoptosis, and improved cardiac function in STZ-induced diabetic mice. Furthermore, NEU1 inhibition also attenuated the high glucose-induced increased reactive oxygen species generation, inflammation and, cell death . ShNEU1 activated Sirtuin 3 (SIRT3) signaling pathway, and SIRT3 deficiency blocked shNEU1-mediated cardioprotective effects . More importantly, we found AMPKα was responsible for the elevation of SIRT3 expression via AMPKα-deficiency studies and . Knockdown of LKB1 reversed the effect elicited by shNEU1 . In conclusion, NEU1 inhibition activates AMPKα via LKB1, and subsequently activates sirt3, thereby regulating fibrosis, inflammation, apoptosis and oxidative stress in diabetic myocardial tissue.
Topics: AMP-Activated Protein Kinases; Animals; Animals, Newborn; Apoptosis; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Fibrosis; Inflammation; Male; Mice; Mice, Inbred C57BL; Mucolipidoses; Myocardium; Neuraminidase; Oxidative Stress; Rats; Signal Transduction; Sirtuin 3; Streptozocin
PubMed: 35002528
DOI: 10.7150/ijbs.65938 -
Science (New York, N.Y.) Oct 2022Lysosomes are key degradative compartments of the cell. Transport to lysosomes relies on GlcNAc-1-phosphotransferase-mediated tagging of soluble enzymes with mannose...
Lysosomes are key degradative compartments of the cell. Transport to lysosomes relies on GlcNAc-1-phosphotransferase-mediated tagging of soluble enzymes with mannose 6-phosphate (M6P). GlcNAc-1-phosphotransferase deficiency leads to the severe lysosomal storage disorder mucolipidosis II (MLII). Several viruses require lysosomal cathepsins to cleave structural proteins and thus depend on functional GlcNAc-1-phosphotransferase. We used genome-scale CRISPR screens to identify lysosomal enzyme trafficking factor (LYSET, also named TMEM251) as essential for infection by cathepsin-dependent viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). LYSET deficiency resulted in global loss of M6P tagging and mislocalization of GlcNAc-1-phosphotransferase from the Golgi complex to lysosomes. knockout mice exhibited MLII-like phenotypes, and human pathogenic LYSET alleles failed to restore lysosomal sorting defects. Thus, LYSET is required for correct functioning of the M6P trafficking machinery and mutations in LYSET can explain the phenotype of the associated disorder.
Topics: Animals; COVID-19; Cathepsins; Humans; Lysosomes; Mannose; Mice; Mice, Knockout; Mucolipidoses; Proteins; Transferases (Other Substituted Phosphate Groups)
PubMed: 36074821
DOI: 10.1126/science.abn5648 -
Bone Feb 2021The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to... (Review)
Review
The hips are frequently involved in inheritable diseases which affect the bones. The clinical and radiological presentation of these diseases may be very similar to common hip disorders as developmental dysplasia of the hip, osteoarthritis and avascular necrosis, so the diagnosis may be easily overlooked and treatment may be suboptimal. Mucopolysaccharidosis (MPS) and Mucolipidosis (ML II and III) are lysosomal storage disorders with multisystemic involvement. Characteristic skeletal abnormalities, known as dysostosis multiplex, are common in MPS and ML and originate from intra-lysosomal storage of glycosaminoglycans in cells of the cartilage, bones and ligaments. The hip joint is severely affected in MPS and ML. Hip pathology results in limitations in mobility and pain from young age, and negatively affects quality of life. In order to better understand the underlying process that causes hip disease in MPS and ML, this review first describes the normal physiological (embryonic) hip joint development, including the interplay between the acetabulum and the femoral head. In the second part the factors contributing to altered hip morphology and function in MPS and ML are discussed, such as abnormal development of the pelvic- and femoral bones (which results in altered biomechanical forces) and inflammation. In the last part of this review therapeutic options and future perspectives are addressed.
Topics: Acetabulum; Hip Joint; Humans; Mucolipidoses; Mucopolysaccharidoses; Quality of Life
PubMed: 33130340
DOI: 10.1016/j.bone.2020.115729