Interplay between protein glycosylation pathways in Alzheimer's disease.
Ontology highlight
ABSTRACT:
SUBMITTER: Frenkel-Pinter M
PROVIDER: S-EPMC5600531 | biostudies-literature | 2017 Sep
REPOSITORIES: biostudies-literature
Publications
Interplay between protein glycosylation pathways in Alzheimer's disease.
Frenkel-Pinter Moran M Shmueli Merav Daniel MD Raz Chen C Yanku Michaela M Zilberzwige Shai S Gazit Ehud E Segal Daniel D
Science advances 20170915 9
Deviations from the normal nucleoplasmic protein O-GlcNAcylation, as well as from normal protein sialylation and N-glycosylation in the secretory pathway, have been reported in Alzheimer's disease (AD). However, the interplay between the cytoplasmic protein <i>O</i>-GlcNAcylation and the secretory N-/O-glycosylation in AD has not been described. We present a comprehensive analysis of the N-, O-, and <i>O</i>-GlcNAc-glycomes in AD-affected brain regions as well as in AD patient serum. We detected ...[more]
Similar Datasets
Project description:Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger and a key molecule in many important signaling cascades in the body and brain, including phototransduction, olfaction, vasodilation, and functional hyperemia. Additionally, cGMP is involved in long-term potentiation (LTP), a cellular correlate of learning and memory, and recent studies have identified the cGMP-increasing drug Sildenafil as a potential risk modifier in Alzheimer's disease (AD). AD development is accompanied by a net increase in the expression of nitric oxide (NO) synthases but a decreased activity of soluble guanylate cyclases, so the exact sign and extent of AD-mediated imbalance remain unclear. Moreover, human patients and mouse models of the disease present with entangled deregulation of both cGMP and Ca2+ signaling, e.g., causing changes in cGMP-mediated Ca2+ release from the intracellular stores as well as Ca2+-mediated cGMP production. Still, the mechanisms governing such interplay are poorly understood. Here, we review the recent data on mechanisms underlying the brain cGMP signaling and its interconnection with Ca2+ signaling. We also discuss the recent evidence stressing the importance of such interplay for normal brain function as well as in Alzheimer's disease.
| S-EPMC9266933 | biostudies-literature
Project description:Alzheimer's disease (AD) is a neurodegenerative disorder, affecting millions of people worldwide, a number expected to exponentially increase in the future since no effective treatments are available so far. AD is characterized by severe cognitive dysfunctions associated with neuronal loss and connection disruption, mainly occurring in specific brain areas such as the hippocampus, cerebral cortex, and amygdala, compromising memory, language, reasoning, and social behavior. Proteomics and redox proteomics are powerful techniques used to identify altered proteins and pathways in AD, providing relevant insights on cellular pathways altered in the disease and defining novel targets exploitable for drug development. Here, we review the main results achieved by both -omics techniques, focusing on the changes occurring in AD mitochondria under oxidative stress and upon copper exposure. Relevant information arises by the comparative analysis of these results, evidencing alterations of common mitochondrial proteins, metabolic cycles, and cascades. Our analysis leads to three shared mitochondrial proteins, playing key roles in metabolism, ATP generation, oxidative stress, and apoptosis. Their potential as targets for development of innovative AD treatments is thus suggested. Despite the relevant efforts, no effective drugs against AD have been reported so far; nonetheless, various compounds targeting mitochondria have been proposed and investigated, reporting promising results.
| S-EPMC8146034 | biostudies-literature
Project description:Protein O-glycosylation is controlled by polypeptide GalNAc-transferases (GalNAc-Ts) that uniquely feature both a catalytic and lectin domain. The underlying molecular basis of how the lectin domains of GalNAc-Ts contribute to glycopeptide specificity and catalysis remains unclear. Here we present the first crystal structures of complexes of GalNAc-T2 with glycopeptides that together with enhanced sampling molecular dynamics simulations demonstrate a cooperative mechanism by which the lectin domain enables free acceptor sites binding of glycopeptides into the catalytic domain. Atomic force microscopy and small-angle X-ray scattering experiments further reveal a dynamic conformational landscape of GalNAc-T2 and a prominent role of compact structures that are both required for efficient catalysis. Our model indicates that the activity profile of GalNAc-T2 is dictated by conformational heterogeneity and relies on a flexible linker located between the catalytic and the lectin domains. Our results also shed light on how GalNAc-Ts generate dense decoration of proteins with O-glycans.
| S-EPMC4432651 | biostudies-literature
Project description:The brain is an organ in which energy metabolism occurs most intensively and glucose is an essential and dominant energy substrate. There have been many studies in recent years suggesting a close relationship between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) as they have many pathophysiological features in common. The condition of hyperglycemia exposes brain cells to the detrimental effects of glucose, increasing protein glycation and is the cause of different non-psychiatric complications. Numerous observational studies show that not only hyperglycemia but also blood glucose levels near lower fasting limits (72 to 99 mg/dL) increase the incidence of AD, regardless of whether T2DM will develop in the future. As the comorbidity of these diseases and earlier development of AD in T2DM sufferers exist, new AD biomarkers are being sought for etiopathogenetic changes associated with early neurodegenerative processes as a result of carbohydrate disorders. The S100B protein seem to be interesting in this respect as it may be a potential candidate, especially important in early diagnostics of these diseases, given that it plays a role in both carbohydrate metabolism disorders and neurodegenerative processes. It is therefore necessary to clarify the relationship between the concentration of the S100B protein and glucose and insulin levels. This paper draws attention to a valuable research objective that may in the future contribute to a better diagnosis of early neurodegenerative changes, in particular in subjects with T2DM and may be a good basis for planning experiments related to this issue as well as a more detailed explanation of the relationship between the neuropathological disturbances and changes of glucose and insulin concentrations in the brain.
| S-EPMC7215807 | biostudies-literature
Project description:Alzheimer's disease (AD) and ischemic stroke (IS) are an immense socioeconomic burden worldwide. There is a possibility that shared genetic factors lead to their links at epidemiological and pathophysiological levels. Although recent genome-wide association studies (GWAS) have provided profound insights into the genetics of AD and IS, no shared genetic variants have been identified to date. This prompted us to initiate this study, which sought to identify shared pathways linking AD and IS. We took advantage of large-scale GWAS summary data of AD (17,008 AD cases and 37,154 controls) and IS (10,307 cases and 19,326 controls) to conduct pathway analyses using genetic pathways from multiple well-studied databases, including GO, KEGG, PANTHER, Reactome, and Wikipathways. Collectively, we discovered that AD and IS shared 179 GO categories (56 biological processes, 95 cellular components, and 28 molecular functions); and the following pathways: six KEGG pathways; two PANTHER pathways; four Reactome pathways; and one in Wikipathways pathway. The more fine-grained GO terms were mainly summarized into different functional categories: transcriptional and post-transcriptional regulation, synapse, endocytic membrane traffic through the endosomal system, signaling transduction, immune process, multi-organism process, protein catabolic metabolism, and cell adhesion. The shared pathways were roughly classified into three categories: immune system; cancer (NSCLC and glioma); and signal transduction pathways involving the cadherin signaling pathway, Wnt signaling pathway, G-protein signaling and downstream signaling mediated by phosphoinositides (PIPs). The majority of these common pathways linked to both AD and IS were supported by convincing evidence from the literature. In conclusion, our findings contribute to a better understanding of common biological mechanisms underlying AD and IS and serve as a guide to direct future research.
| S-EPMC6137293 | biostudies-literature
Project description:This study aims to investigate the relationship between structural changes in the retina and white matter in the brain, in early Alzheimer's disease (AD). Twenty-three healthy controls (mean age = 63.4±7.5 years) and seventeen AD patients (mean age = 66.5±6.6 years) were recruited for this study. By combining two imaging techniques-optical coherence tomography and diffusion tensor imaging (DTI)-the association between changes in the thickness of individual retinal layers and white matter dysfunction in early AD was assessed. Retinal layers were segmented, and thickness measurements were obtained for each layer. DTI images were analyzed with a quantitative data-driven approach to evaluating whole-brain diffusion metrics, using tract-based spatial statistics. Diffusion metrics, such as fractional anisotropy, are markers for white matter integrity. Multivariate and partial correlation analyses evaluating the association between individual retinal layers thickness and diffusion metrics were performed. We found that axial diffusivity, indexing axonal integrity, was significantly reduced in AD (p = 0.016, Cohen's d = 1.004) while in the retina, only a marginal trend for significance was found for the outer plexiform layer (p = 0.084, Cohen's d = 0.688). Furthermore, a positive association was found in the AD group between fractional anisotropy and the inner nuclear layer thickness (p < 0.05, r = 0.419, corrected for multiple comparisons by controlling family-wise error rate). Our findings suggest that axonal damage in the brain dominates early on in this condition and shows an association with retinal structural integrity already at initial stages of AD. These findings are consistent with an early axonal degeneration mechanism in AD.
| S-EPMC6700635 | biostudies-literature
Project description:BACKGROUND:The amyloid precursor protein (APP) is a transmembrane glycoprotein that undergoes alternative proteolytic processing. Its processing through the amyloidogenic pathway originates a large sAPP? ectodomain fragment and the ?-amyloid peptide, while non-amyloidogenic processing generates sAPP? and shorter non-fibrillar fragments. Hence, measuring sAPP? and sAPP? has been proposed as a means to identify imbalances between the amyloidogenic/non-amyloidogenic pathways in the brain of Alzheimer's disease (AD) patients. However, to date, no consistent changes in these proteolytic fragments have been identified in either the brain or cerebrospinal fluid of AD individuals. METHODS:In frontal cortex homogenates from AD patients (n?=?7) and non-demented controls (NDC; n?=?7), the expression of total APP mRNA and that of the APP isoforms generated by alternative splicing, APP695 and APP containing the Kunitz protease inhibitor (KPI), was analyzed by qRT-PCR using TaqMan and SYBR Green probes. The balance between the amyloidogenic/non-amyloidogenic pathways was examined in western blots estimating the sAPP? and sAPP? fragments and their membrane-tethered C-terminal fragments CTF? and CTF?. CHO-PS70 cells, stably over-expressing wild-type human APP, served to evaluate whether A?42 peptide treatment results in altered APP glycosylation. We determined the glycosylation pattern of sAPP? and sAPP? in brain extracts and CHO-PS70 culture media by lectin-binding assays. RESULTS:In the cortex of AD patients, we detected an increase in total APP mRNA relative to the controls, due to an increase in both the APP695 and APP-KPI variants. However, the sAPP? or sAPP? protein levels remained unchanged, as did those of CTF? and CTF?. We studied the glycosylation of the brain sAPP? and sAPP? using lectins and pan-specific antibodies to discriminate between the fragments originated from neuronal APP695 and glial/KPI variants. Lectin binding identified differences in the glycosylation of sAPP? species derived from the APP695 and APP-KPI variants, probably reflecting their distinct cellular origin. Moreover, the lectin-binding pattern differed in the sAPP? and sAPP? originated from all the variants. Finally, when the lectin-binding pattern was compared between AD and NDC groups, significant differences were evident in sAPP? glycosylation. Lectin binding of the soluble sAPP? and sAPP? from CHO-PS70 cells were also altered in cells treated with the A? peptide. CONCLUSION:Our analysis of the lectin binding to sAPP? and sAPP? suggests that glycosylation dictates the proteolytic pathway for APP processing. Differences between the demented and controls indicate that changes in glycosylation may influence the generation of the different APP fragments and, consequently, the pathological progression of AD.
| S-EPMC7425076 | biostudies-literature
Project description:Protein N-glycosylation plays critical roles in controlling brain function, but little is known about human brain N-glycoproteome and its alterations in Alzheimer's disease (AD). Here, we report the first, large-scale, site-specific N-glycoproteome profiling study of human AD and control brains using mass spectrometry-based quantitative N-glycoproteomics. The study provided a system-level view of human brain N-glycoproteins and in vivo N-glycosylation sites and identified disease signatures of altered N-glycopeptides, N-glycoproteins, and N-glycosylation site occupancy in AD. Glycoproteomics-driven network analysis showed 13 modules of co-regulated N-glycopeptides/glycoproteins, 6 of which are associated with AD phenotypes. Our analyses revealed multiple dysregulated N-glycosylation-affected processes and pathways in AD brain, including extracellular matrix dysfunction, neuroinflammation, synaptic dysfunction, cell adhesion alteration, lysosomal dysfunction, endocytic trafficking dysregulation, endoplasmic reticulum dysfunction, and cell signaling dysregulation. Our findings highlight the involvement of N-glycosylation aberrations in AD pathogenesis and provide new molecular and system-level insights for understanding and treating AD.
| S-EPMC7852392 | biostudies-literature
Project description:BackgroundProtein glycosylation has been confirmed to be involved in the pathological mechanisms of Alzheimer's disease (AD); however, there is still a lack of systematic analysis of the immune processes mediated by protein glycosylation-related genes (PGRGs) in AD.Materials and methodsTranscriptomic data of AD patients were obtained from the Gene Expression Omnibus database and divided into training and verification datasets. The core PGRGs of the training set were identified by weighted gene co-expression network analysis, and protein glycosylation-related subtypes in AD were identified based on k-means unsupervised clustering. Protein glycosylation scores and neuroinflammatory levels of different subtypes were compared, and functional enrichment analysis and drug prediction were performed based on the differentially expressed genes (DEGs) between the subtypes. A random forest model was used to select important DEGs as diagnostic markers between subtypes, and a line chart model was constructed and verified in other datasets. We evaluated the differences in immune cell infiltration between the subtypes through the single-sample gene set enrichment analysis, analyzed the correlation between core diagnostic markers and immune cells, and explored the expression regulation network of the core diagnostic markers.ResultsEight core PGRGs were differentially expressed between the training set and control samples. AD was divided into two subtypes with significantly different biological processes, such as vesicle-mediated transport in synapses and neuroactive ligand-receptor interactions. The high protein glycosylation subtype had a higher level of neuroinflammation. Riluzole and sulfasalazine were found to have potential clinical value in this subtype. A reliable construction line chart model was constructed based on nine diagnostic markers, and SERPINA3 was identified as the core diagnostic marker. There were significant differences in immune cell infiltration between the two subtypes. SERPINA3 was found to be closely related to immune cells, and the expression of SERPINA3 in AD was found to be regulated by a competing endogenous RNA network that involves eight long non-coding RNAs and seven microRNAs.ConclusionProtein glycosylation and its corresponding immune process play an important role in the occurrence and development of AD. Understanding the role of PGRGs in AD may provide a new potential therapeutic target for AD.
| S-EPMC9667030 | biostudies-literature
Project description:Calcium (Ca2+) homeostasis is essential for cell maintenance since this ion participates in many physiological processes. For example, the spatial and temporal organization of Ca2+ signaling in the central nervous system is fundamental for neurotransmission, where local changes in cytosolic Ca2+ concentration are needed to transmit information from neuron to neuron, between neurons and glia, and even regulating local blood flow according to the required activity. However, under pathological conditions, Ca2+ homeostasis is altered, with increased cytoplasmic Ca2+ concentrations leading to the activation of proteases, lipases, and nucleases. This review aimed to highlight the role of Ca2+ signaling in neurodegenerative disease-related apoptosis, where the regulation of intracellular Ca2+ homeostasis depends on coordinated interactions between the endoplasmic reticulum, mitochondria, and lysosomes, as well as specific transport mechanisms. In neurodegenerative diseases, alterations-increased oxidative stress, energy metabolism alterations, and protein aggregation have been identified. The aggregation of ?-synuclein, ?-amyloid peptide (A?), and huntingtin all adversely affect Ca2+ homeostasis. Due to the mounting evidence for the relevance of Ca2+ signaling in neuroprotection, we would focus on the expression and function of Ca2+ signaling-related proteins, in terms of the effects on autophagy regulation and the onset and progression of neurodegenerative diseases.
| S-EPMC6928941 | biostudies-literature