O -GlcNAc and Neurodegeneration: Biochemical Mechanisms and Potential Roles in Alzheimer\u27s Disease and Beyond

Alzheimer disease (AD) is a growing problem for aging populations worldwide. Despite significant efforts, no therapeutics are available that stop or slow progression of AD, which has driven interest in the basic causes of AD and the search for new therapeutic strategies. Longitudinal studies have clarified that defects in glucose metabolism occur in patients exhibiting Mild Cognitive Impairment (MCI) and glucose hypometabolism is an early pathological change within AD brain. Further, type 2 diabetes mellitus (T2DM) is a strong risk factor for the development of AD. These findings have stimulated interest in the possibility that disrupted glucose regulated signaling within the brain could contribute to the progression of AD. One such process of interest is the addition of O-linked N-acetylglucosamine (O-GlcNAc) residues onto nuclear and cytoplasmic proteins within mammals. O-GlcNAc is notably abundant within brain and is present on hundreds of proteins including several, such as tau and the amyloid precursor protein, which are involved in the pathophysiology AD. The cellular levels of O-GlcNAc are coupled to nutrient availability through the action of just two enzymes. O-GlcNAc transferase (OGT) is the glycosyltransferase that acts to install O-GlcNAc onto proteins and O-GlcNAcase (OGA) is the glycoside hydrolase that acts to remove O-GlcNAc from proteins. Uridine 5′-diphosphate-N-acetylglucosamine (UDP-GlcNAc) is the donor sugar substrate for OGT and its levels vary with cellular glucose availability because it is generated from glucose through the hexosamine biosynthetic pathway (HBSP). Within the brains of AD patients O-GlcNAc levels have been found to be decreased and aggregates of tau appear to lack O-GlcNAc entirely. Accordingly, glucose hypometabolism within the brain may result in disruption of the normal functions of O-GlcNAc within the brain and thereby contribute to downstream neurodegeneration. While this hypothesis remains largely speculative, recent studies using different mouse models of AD have demonstrated the protective benefit of pharmacologically increased brain O-GlcNAc levels. In this review we summarize the state of knowledge in the area of O-GlcNAc as it pertains to AD while also addressing some of the basic biochemical roles of O-GlcNAc and how these might contribute to protecting against AD and other neurodegenerative diseases

Ion homeostasis in the Chloroplast

peer reviewedThe chloroplast is an organelle of high demand for macro- and micro-nutrient ions, which are required for the maintenance of the photosynthetic process. To avoid deficiency while preventing excess, homeostasis mechanisms must be tightly regulated. Here, we describe the needs for nutrient ions in the chloroplast and briefly highlight their functions in the chloroplastidial metabolism. We further discuss the impact of nutrient deficiency on chloroplasts and the acclimation mechanisms that evolved to preserve the photosynthetic apparatus. We finally present what is known about import and export mechanisms for these ions. Whenever possible, a comparison between cyanobacteria, algae and plants is provided to add an evolutionary perspective to the description of ion homeostasis mechanisms in photosynthesis

A generalized Dynamic Energy Budget model including 3D shape changes for modeling small pelagic fish growth

International audienceSmall pelagic fish (SPF) are key components of marine ecosystems, transporting energy from the lower to the upper trophic levels and thereby influencing the dynamics of the entire ecosystem. Understanding their complex growth patterns from early life stages to adulthood is fundamental to accurately predict larval survival and predator-prey dynamics, which are influenced by individual size. However, growth models are generally unable to accurately reproduce the growth acceleration and deceleration phases observed, particularly during early life stages. Here we propose a growth model based on a Dynamic Energy Budget model (modified as in Maury, 2019 to properly account for size-dependence of maintenance) that captures deviations from pure isomorphy. It represents the fish’s body as an ellipsoid and differentially allocates volumetric growth to length, height and width as a function of the distance between the current shape and characteristic stage-dependent shape attractors (expressed as width/length and height/width ratios). The resulting surface-to-volume ratios mechanistically explain the “metabolic acceleration” often invoked to explain early life growth patterns. We estimated model parameters for three important SPF species in the Benguela upwelling system, using data covering growth at all life-stages, transitions between life-stages, and reproduction. The calibrated models reproduced the observed deviations from isomorphy, with exponential length-dominated growth until metamorphosis, then a shift to height- and width-dominated growth (with a corresponding deceleration of length growth) until the adult shape is reached, and finally isomorphic (characteristic von Bertalanffy) length growth. These deviations from the usual von Bertalanffy growth model could profoundly affect our understanding of larval survival, predator-prey and ecosystem-dynamic

A generalized Dynamic Energy Budget model including 3D shape changes for modeling small pelagic fish growth

Small pelagic fish (SPF) are key components of marine ecosystems, transporting energy from the lower to the upper trophic levels and thereby influencing the dynamics of the entire ecosystem. Understanding their complex growth patterns from early life stages to adulthood is fundamental to accurately predict larval survival and predator-prey dynamics, which are influenced by individual size. However, growth models are generally unable to accurately reproduce the growth acceleration and deceleration phases observed, particularly during early life stages. Here we propose a growth model based on a Dynamic Energy Budget model (modified as in Maury, 2019 to properly account for size-dependence of maintenance) that captures deviations from pure isomorphy. It represents the fish’s body as an ellipsoid and differentially allocates volumetric growth to length, height and width as a function of the distance between the current shape and characteristic stage-dependent shape attractors (expressed as width/length and height/width ratios). The resulting surface-to-volume ratios mechanistically explain the “metabolic acceleration” often invoked to explain early life growth patterns. We estimated model parameters for three important SPF species in the Benguela upwelling system, using data covering growth at all life-stages, transitions between life-stages, and reproduction. The calibrated models reproduced the observed deviations from isomorphy, with exponential length-dominated growth until metamorphosis, then a shift to height- and width-dominated growth (with a corresponding deceleration of length growth) until the adult shape is reached, and finally isomorphic (characteristic von Bertalanffy) length growth. These deviations from the usual von Bertalanffy growth model could profoundly affect our understanding of larval survival, predator-prey and ecosystem-dynamic