O-GlcNAcase contributes to cognitive function in Drosophila

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Process of psychological adjustment to multiple sclerosis: comparing the roles of appraisals, acceptance, and cognitive fusion.

Background: Research in psychological adjustment to multiple sclerosis (MS) suggests that the way individuals appraise their condition can have an impact upon their psychological well-being and adjustment to their condition. Such research has influenced the development of Cognitive Behavioural Therapy (CBT) interventions in this population. In recent years, Acceptance and Commitment Therapy (ACT) has gathered increasing interest in relation to chronic health conditions. ACT does not target the content of thought, but rather focuses on the contexts in which thought occurs (i.e. how individuals relate to their experiences). Aim and Primary Hypothesis: A cross sectional design was used to compare the extent to which cognitive appraisals and ACT constructs (‘acceptance’ and ‘cognitive fusion’), mediate the relationship between physical symptoms of MS and psychological adjustment outcomes. It was hypothesised that in comparison to cognitive appraisals, ACT constructs would serve as stronger mediators of the relationship between physical symptoms of MS and outcome measures. This study also piloted a newly adapted measure of MS related acceptance, the Multiple Sclerosis Acceptance Questionnaire (MSAQ). Method and Results: Participants (N = 133) completed self-report measures of: MS symptom severity, various cognitive constructs (cognitive appraisals and ACT constructs), symptoms of psychological distress, and satisfaction with life. Multiple mediation analysis was then used to compare competing mediational hypotheses. In comparison to all measures of cognitive appraisals, the ACT constructs tended to be stronger mediators of the relationship between symptoms and outcome measures (both psychological distress, and satisfaction with life). There was also some evidence for appraisals of personal control mediating the relationship between symptoms of MS and psychological distress. Conclusions: This research suggests that ACT constructs may be relevant to the process of psychological adjustment to MS, and that ACT based interventions may be worthy of investigation in this population. The newly adapted MSAQ also shows preliminary promise as a measure of MS related acceptance

Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability

The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred to as O-GlcNAcylation) is a modification that is crucial for vertebrate development. O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense variants of OGT have recently been shown to segregate with an X-linked syndromic form of intellectual disability, OGT-linked congenital disorder of glycosylation (OGT-CDG). Although the existence of OGT-CDG suggests that O-GlcNAcylation is crucial for neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and reduced levels of OGT and OGA in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlations in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.</p

Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability

The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred to as O-GlcNAcylation) is a modification that is crucial for vertebrate development. O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense variants of OGT have recently been shown to segregate with an X-linked syndromic form of intellectual disability, OGT-linked congenital disorder of glycosylation (OGT-CDG). Although the existence of OGT-CDG suggests that O-GlcNAcylation is crucial for neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and reduced levels of OGT and OGA in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlations in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.</p

The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis

In this review, we examine senescent cells and the overlap between the direct biological impact of senescence and the indirect impact senescence has via its effects on other cell types, particularly the macrophage. The canonical roles of macrophages in cell clearance and in other physiological functions are discussed with reference to their functions in diseases of the kidney and other organs. We also explore the translational potential of different approaches based around the macrophage in future interventions to target senescent cells, with the goal of preventing or reversing pathologies driven or contributed to in part by senescent cell load in vivo

Genetic recoding to dissect the roles of site-specific protein O-GlcNAcylation

ISSN:1559-744XISSN:1559-743

O-GlcNAcase Fragment Discovery with Fluorescence Polarimetry

The attachment of the sugar N-acetyl-D-glucosamine (GlcNAc) to specific serine and threonine residues on proteins is referred to as protein O-GlcNAcylation. O-GlcNAc transferase (OGT) is the enzyme responsible for carrying out the modification, while O-GlcNAcase (OGA) reverses it. Protein O-GlcNAcylation has been implicated in a wide range of cellular processes including transcription, proteostasis, and stress response. Dysregulation of O-GlcNAc has been linked to diabetes, cancer, and neurodegenerative and cardiovascular disease. OGA has been proposed to be a drug target for the treatment of Alzheimer’s and cardiovascular disease given that increased O-GlcNAc levels appear to exert a protective effect. The search for specific, potent, and drug-like OGA inhibitors with bioavailability in the brain is therefore a field of active research, requiring orthogonal high-throughput assay platforms. Here, we describe the synthesis of a novel probe for use in a fluorescence polarization based assay for the discovery of inhibitors of OGA. We show that the probe is suitable for use with both human OGA, as well as the orthologous bacterial counterpart from <i>Clostridium perfringens</i>, <i>Cp</i>OGA, and the lysosomal hexosaminidases HexA/B. We structurally characterize <i>Cp</i>OGA in complex with a ligand identified from a fragment library screen using this assay. The versatile synthesis procedure could be adapted for making fluorescent probes for the assay of other glycoside hydrolases