Since glycosylation depends on glycosyltransferases, glycosidases, and sugar nucleotide donors, it is susceptible to the changes associated with physiological and pathological conditions. Therefore, ...alterations in glycan structures may be good targets and biomarkers for monitoring health conditions. Since human aging and longevity are affected by genetic and environmental factors such as diseases, lifestyle, and social factors, a scale that reflects various environmental factors is required in the study of human aging and longevity.
We herein focus on glycosylation changes elucidated by glycomic and glycoproteomic studies on aging, longevity, and age-related diseases including cognitive impairment, diabetes mellitus, and frailty. We also consider the potential of glycan structures as biomarkers and/or targets for monitoring physiological and pathophysiological changes.
Glycan structures are altered in age-related diseases. These glycans and glycoproteins may be involved in the pathophysiology of these diseases and, thus, be useful diagnostic markers. Age-dependent changes in N-glycans have been reported previously in cohort studies, and characteristic N-glycans in extreme longevity have been proposed. These findings may lead to a deeper understanding of the mechanisms underlying aging as well as the factors influencing longevity.
Alterations in glycosylation may be good targets and biomarkers for monitoring health conditions, and be applicable to studies on age-related diseases and healthy aging. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.
•Glycan changes in aging, longevity, and age-related diseases have been reviewed.•Glycomics and glycoproteomics are powerful tools for monitoring health conditions.•Changes in glycosylation are applicable to studies on human aging and longevity.
The demographic structure of a country changes dramatically with increasing trends toward general population aging and declining birth rates. In Japan, the percentage of the elderly population (aged ...≥65 years) reached 25% in 2013; it is expected to exceed 30% in 2025 and reach 39.9% in 2060. The national total population has been decreasing steadily since its peak reached in 2008, and it is expected to fall to the order of 80 million in 2060. Of the total population, those aged ≥75 years accounted for 12.3% as of 2013, and this is expected to reach 26.9% in 2060. As the demographic structure changes, the disease structure changes, and therefore the medical care demand changes. To accommodate the medical care demand changes, it is necessary to secure a system for providing medical care. Japan has thus far attained remarkable achievements in medical care, seeking a better prognosis for survival; however, its medical care demand is anticipated to change both qualitatively and quantitatively. As diseases in the elderly, particularly in the old-old population, are often intractable, conventional medical care must be upgraded to one suitable for an aged society. What is required to this end is a shift from "cure-seeking medical care" focusing on disease treatment on an organ-specific basis to "cure and support-seeking medical care" with treatments reprioritized to maximize the quality of life (QOL) for the patient, or a change from "hospital-centered medical care" to "community-oriented medical care" in correlation with nursing care and welfare.
(1) Necessity for a paradigm shift to "cure-and-support seeking medical care" In addition to the process of aging with functional deterioration of multiple organs, the elderly often suffer from systemically disordering diseases, such as lifestyle-related diseases, as well as geriatric syndrome and daily activity dysfunction; therefore, integrated and comprehensive medical care is required. In addition, with regard to diseases in the elderly, not only their acute stage, but also their chronic and intermediate stages must be emphasized in their treatment. Aiming to achieve a complete cure of disease by exploring the cause and implementing radical treatment, the conventional medical care model is difficult to apply to the medical care of the elderly; medical care suitable for the elderly is required. (2) Spread of home-based care and the necessity for human resources development Many elderly people want to continue to live in their house and their community where they have been living for a long time, even with disease. There are increasing needs for QOL-emphasizing home-based care for patients in the intermediate stage after completion of acute stage treatment, or for end-of-life care. Hence, there is a demand for a shift to "community-oriented medical care" for providing comprehensive care supported with medical and nursing resources available in the community. As the percentage of the elderly population (aged ≥65 years) and the availability of medical care resources vary considerably among different regions, it is important that specialists in the fields of public health, medical care, nursing care, and welfare work on establishing a collaborative system suitable for the local characteristics of each region by making the best use of their own specialties. (3) Necessity for establishing a department of gerontology or geriatric medicine at each medical school In line with the increasing number of elderly people, it is necessary to upgrade the systems for educating and nurturing physicians engaged in healthcare and nursing care for the elderly. It is also necessary to develop the organic cooperation with other medical and nursing care professionals, such as registered nurses and care workers. At present, just approximately 30% of medical schools in Japan have a department specializing in medical care for the elderly and relevant medical education; there is an urgent need to improve the situation, as the majority of universities do not provide any such education. (4) Necessity for establishing a medical center for promoting medical care provider collaboration, multidisciplinary training and a means to increase public awareness In the medical care for the elderly, comprehensive care must be provided from the viewpoints of both healthcare and nursing care; to improve the quality of such care services, multidisciplinary collaboration and team-based medicine are indispensable. Therefore, physicians, nurses, therapists, pharmacists, dieticians, care managers, and other health care professionals who have thorough knowledge about medical care for the elderly are of utmost necessity. In reality, however, the collaboration of these health care professionals is unsatisfactory, and the degree of understanding of team-based medicine by each medical professional is low. Therefore, as in the case of the establishment of cancer centers within individual regions to promote medical care for cancer, there is a demand to nurture professionals engaged in medical care for the elderly, and to establish a core facility for the promotion of multidisciplinary collaboration and team-based medicine for each region. (5) Do the people understand the paradigm shift? Currently, not only healthcare professionals, but also many citizens seek "cure-seeking medical care" aiming at a restoration of organ function; however, surveys of the elderly often show that they want to restore independent daily activity, rather than to achieve a "cure." In contrast, in the actual medical care setting, contradictory situations prevail in which the public awareness of the shift to "cure-and-support seeking medical care" is unsatisfactory, including the fact that the majority of recipients of tertiary emergency care are elderly patients.
The Science Council of Japan has the task to propose future visions for the Japanese aging society not only from the viewpoint of the health of each individual, but also from a broader perspective, taking into account the relationship between humans and society. Various issues related to general population aging are posing serious problems, which require prompt resolution. Although we made a number of proposals at the 21st Subcommittee for Aging, the situation has not changed satisfactorily. Accordingly, the present proposals on specific solutions were designed. (1) In a super-aged society, a paradigm shift to "cure-and-support seeking medical care" should be implemented A super-aged society will consist of an unprecedented demographic structure in which the percentage of only those people aged ≥75 years will increase in the entire population. Therefore, there is an urgent need to prepare for increasing populations of persons in need of long-term care and those who are likely to become in need of long-term care. Given the consideration that "patients are not merely sick persons, but rather living persons," a paradigm shift from conventional "cure-seeking medical care" to "cure and support-seeking medical care" must be implemented. (2) Facilitate a paradigm shift to community-oriented medical care, and promote the activity of female physicians in the medical care for the elderly A paradigm shift should be promptly facilitated by reorganizing hospital functions and establishing a community comprehensive care system for home-based care to promote the participation of the elderly by themselves in care-supporting society. To further promote the collaboration of medical care and welfare, not only persons in charge of actual regional settings, but also university schools of medicine and regional core medical institutions experienced in medical care for the elderly should take the initiative to promote home-based care and facilitate a paradigm shift to community-oriented medical care. In addition, programs should also be developed to re-educate female physicians who became housewives in order to nurture them to become facilitators of geriatric medicine. (3) Physicians who are required at local medical facilities must be nurtured through the establishment of a department of gerontology or geriatric medicine at each medical school To facilitate efficient medical care services, medical education and research, and human resources development in support of expected paradigm shifts, it is considered that a department of gerontology or geriatric medicine should be established at each medical school. Furthermore, it is necessary to allocate dedicated teachers of medical care for the elderly to all medical schools, as well as to upgrade practice-participatory drills and to collaborate with a broad range of entities, including local medical institutions, and welfare and nursing care facilities. Efforts must be made to nurture locally wanted physicians through specific efforts concerning team-based medicine. (4) Promote the establishment of centers for geriatrics and gerontology (provisional name) for medical care collaboration, multidisciplinary training, and a means to increase public awareness To promote the uniform accessibility of expertise on efficient medical care that is best suited for a super-aged society, it is necessary to build a post-graduation educational system under the initiatives of the Japan Geriatrics Society and the National Center for Geriatrics and Gerontology across the nation in cooperation with regional medical schools and the Japan Medical Association. Furthermore, at least one hospital serving as a center for geriatrics and gerontology should be established in each regional block (Hokkaido, Tohoku, Koshinetsu, Hokuriku/Tokai, Kinki, Chushikoku and Kyushu/Okinawa) by making the best use of existing hospitals. By establishing these centers, uniform accessibility for the quality of medical care for the elderly in each region is expected. (ABSTRACT TRUNCATED).
Abstract
α-Dystroglycan (α-DG) is a highly glycosylated cell-surface protein. Defective O-mannosyl glycan on α-DG is associated with muscular dystrophies and cancer. In the biosynthetic pathway of ...the O-mannosyl glycan, fukutin (FKTN) and fukutin-related protein (FKRP) transfer ribitol phosphate (RboP). Previously, we reported that FKTN and FKRP can also transfer glycerol phosphate (GroP) from CDP-glycerol (CDP-Gro) and showed the inhibitory effects of CDP-Gro on functional glycan synthesis by preventing glycan elongation in vitro. However, whether mammalian cells have CDP-Gro or associated synthetic machinery has not been elucidated. Therefore, the function of CDP-Gro in mammals is largely unknown. Here, we reveal that cultured human cells and mouse tissues contain CDP-Gro using liquid chromatography tandem–mass spectrometry (LC–MS/MS). By performing the enzyme activity assay of candidate recombinant proteins, we found that ethanolamine-phosphate cytidylyltransferase (PCYT2), the key enzyme in de novo phosphatidylethanolamine biosynthesis, has CDP-Gro synthetic activity from glycerol-3-phosphate (Gro3P) and CTP. In addition, knockdown of PCYT2 dramatically reduced cellular CDP-Gro. These results indicate that PCYT2 is a CDP-Gro synthase in mammals. Furthermore, we found that the expression of functionally glycosylated α-DG is increased by reducing PCYT2 expression. Our results suggest an important role for CDP-Gro in the regulation of α-DG function in mammals.
Graphical abstract
α-Dystroglycan (α-DG) is a highly-glycosylated surface membrane protein. Defects in the O-mannosyl glycan of α-DG cause dystroglycanopathy, a group of congenital muscular dystrophies. The core M3 ...O-mannosyl glycan contains tandem ribitol-phosphate (RboP), a characteristic feature first found in mammals. Fukutin and fukutin-related protein (FKRP), whose mutated genes underlie dystroglycanopathy, sequentially transfer RboP from cytidine diphosphate-ribitol (CDP-Rbo) to form a tandem RboP unit in the core M3 glycan. Here, we report a series of crystal structures of FKRP with and without donor (CDP-Rbo) and/or acceptor RboP-(phospho-)core M3 peptide substrates. FKRP has N-terminal stem and C-terminal catalytic domains, and forms a tetramer both in crystal and in solution. In the acceptor complex, the phosphate group of RboP is recognized by the catalytic domain of one subunit, and a phosphate group on O-mannose is recognized by the stem domain of another subunit. Structure-based functional studies confirmed that the dimeric structure is essential for FKRP enzymatic activity.
Bacteria contain glycerol phosphate (GroP)-containing glycans, which are important constituents of cell-surface glycopolymers such as the teichoic acids of Gram-positive bacterial cell walls. These ...glycopolymers comprising GroP play crucial roles in bacterial physiology and virulence. Recently, the first identification of a GroP-containing glycan in mammals was reported as a variant form of
-mannosyl glycan on α-dystroglycan (α-DG). However, the biological significance of such GroP modification remains largely unknown. In this review, we provide an overview of this new discovery of GroP-containing glycan in mammals and then outline the recent progress in elucidating the biosynthetic mechanisms of GroP-containing glycans on α-DG. In addition, we discuss the potential biological role of GroP modification along with the challenges and prospects for further research. The progress in this newly identified glycan modification will provide insights into the phylogenetic implications of glycan.
Ribitol-phosphate modification is crucial for the functional maturation of α-dystroglycan. Its dysfunction is associated with muscular dystrophy, cardiomyopathy, and central nervous system ...abnormalities; however, no effective treatments are currently available for diseases caused by ribitol-phosphate defects. In this study, we demonstrate that prodrug treatments can ameliorate muscular dystrophy caused by defects in isoprenoid synthase domain containing (ISPD), which encodes an enzyme that synthesizes CDP-ribitol, a donor substrate for ribitol-phosphate modification. We generated skeletal muscle-selective Ispd conditional knockout mice, leading to a pathogenic reduction in CDP-ribitol levels, abnormal glycosylation of α-dystroglycan, and severe muscular dystrophy. Adeno-associated virus-mediated gene replacement experiments suggested that the recovery of CDP-ribitol levels rescues the ISPD-deficient pathology. As a prodrug treatment strategy, we developed a series of membrane-permeable CDP-ribitol derivatives, among which tetraacetylated CDP-ribitol ameliorated the dystrophic pathology. In addition, the prodrug successfully rescued abnormal α-dystroglycan glycosylation in patient fibroblasts. Consequently, our findings provide proof-of-concept for supplementation therapy with CDP-ribitol and could accelerate the development of therapeutic agents for muscular dystrophy and other diseases caused by glycosylation defects.
Most proteins are modified by glycans, which can modulate the biological properties and functions of glycoproteins. The major glycans can be classified into N-glycans and O-glycans according to their ...glycan-peptide linkage. This review will provide an overview of the O-mannosyl glycans, one subtype of O-glycans. Originally, O-mannosyl glycan was only known to be present on a limited number of glycoproteins, especially α-dystroglycan (α-DG). However, once a clear relationship was established between O-mannosyl glycan and the pathological mechanisms of some congenital muscular dystrophies in humans, research on the biochemistry and pathology of O-mannosyl glycans has been expanding. Because α-DG glycosylation is defective in congenital muscular dystrophies, which also feature abnormal neuronal migration, these disorders are collectively called α-dystroglycanopathies. In this article, I will describe the structure, biosynthesis and pathology of O-mannosyl glycans.
Saliva contains a large number of proteins that participate in the protection of oral tissue. Exosomes are small vesicles (30—100 nm in diameter) with an endosome-derived limiting membrane that are ...secreted by a diverse range of cell types. We have recently demonstrated that exosomes are present in human whole saliva. In this study, we found that whole saliva contained at least two types of exosomes (exosome I and exosome II) that are different in size and protein composition. Proteomic analysis revealed that both types of exosomes contained Alix, Tsg101 and Hsp70, all exosomal markers, immunoglobulin A and polymeric immunoglobulin receptor, whereas they had different protein compositions. Most of dipeptidyl peptidase IV known as CD26 in whole saliva, was present on the exosome II and metabolically active in cleaving chemokines (CXCL11 and CXCL12). Human whole saliva exosomes might participate in the catabolism of bioactive peptides and play a regulatory role in local immune defense in the oral cavity.
Glycosylation is an essential post-translational modification that underlies many biological processes and diseases. α-dystroglycan (α-DG) is a receptor for matrix and synaptic proteins that causes ...muscular dystrophy and lissencephaly upon its abnormal glycosylation (α-dystroglycanopathies). Here we identify the glycan unit ribitol 5-phosphate (Rbo5P), a phosphoric ester of pentose alcohol, in α-DG. Rbo5P forms a tandem repeat and functions as a scaffold for the formation of the ligand-binding moiety. We show that enzyme activities of three major α-dystroglycanopathy-causing proteins are involved in the synthesis of tandem Rbo5P. Isoprenoid synthase domain-containing (ISPD) is cytidine diphosphate ribitol (CDP-Rbo) synthase. Fukutin and fukutin-related protein are sequentially acting Rbo5P transferases that use CDP-Rbo. Consequently, Rbo5P glycosylation is defective in α-dystroglycanopathy models. Supplementation of CDP-Rbo to ISPD-deficient cells restored α-DG glycosylation. These findings establish the molecular basis of mammalian Rbo5P glycosylation and provide insight into pathogenesis and therapeutic strategies in α-DG-associated diseases.
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•Ribitol 5-phosphate is a functional glycan unit in mammals•α-dystroglycan function requires tandem ribitol 5-phosphate structure•Muscular dystrophy proteins are involved in ribitol 5-phosphate glycosylation•Supplementation with ribitol 5-phosphate metabolites may be a therapeutic strategy
Kanagawa et al. show that ribitol 5-phophate is a functional glycan unit in mammals and that defects in its post-translational modification pathway are associated with muscular dystrophy.
The β‐site amyloid precursor protein cleaving enzyme‐1 (BACE1), an essential protease for the generation of amyloid‐β (Aβ) peptide, is a major drug target for Alzheimer's disease (AD). However, there ...is a concern that inhibiting BACE1 could also affect several physiological functions. Here, we show that BACE1 is modified with bisecting N‐acetylglucosamine (GlcNAc), a sugar modification highly expressed in brain, and demonstrate that AD patients have higher levels of bisecting GlcNAc on BACE1. Analysis of knockout mice lacking the biosynthetic enzyme for bisecting GlcNAc, GnT‐III (Mgat3), revealed that cleavage of Aβ‐precursor protein (APP) by BACE1 is reduced in these mice, resulting in a decrease in Aβ plaques and improved cognitive function. The lack of this modification directs BACE1 to late endosomes/lysosomes where it is less colocalized with APP, leading to accelerated lysosomal degradation. Notably, other BACE1 substrates, CHL1 and contactin‐2, are normally cleaved in GnT‐III‐deficient mice, suggesting that the effect of bisecting GlcNAc on BACE1 is selective to APP. Considering that GnT‐III‐deficient mice remain healthy, GnT‐III may be a novel and promising drug target for AD therapeutics.
Synopsis
Bisecting GlcNAc modification of BACE1 by GnT‐III is a novel regulator of BACE1 stability. Loss of GnT‐III curbs BACE1‐mediated Aβ plaque generation. Hence, the bisecting GlcNAc biosynthesis pathway is a promising new target for AD therapy.
Alzheimer's disease (AD) patients present high levels of bisecting GlcNAc modifications on BACE1.
Loss of bisecting GlcNAc reduces BACE1‐mediated Aβ generation, leading to amelioration of AD pathology.
Loss of bisecting GlcNAc reduces BACE1–APP localization.
The enzyme responsible for the biosynthesis of bisecting GlcNAc, GnT‐III, is therefore a potential new drug target for AD.
Bisecting GlcNAc modification of BACE1 by GnT‐III is a novel regulator of BACE1 stability. Loss of GnT‐III curbs BACE1‐mediated Aβ plaque generation. Hence, the bisecting GlcNAc biosynthesis pathway is a promising new target for AD therapy.
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