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  • The nutrient sensing pathway that encompasses the dynamic an

    2019-07-06

    The nutrient-sensing pathway that encompasses the dynamic and reversible post-translational modification called O-linked-β-N-acetylglucosaminylation (O-GlcNAcylation) plays a significant role in disease progression. In fact, O-GlcNAcylation of nuclear, cytoplasmic and mitochondrial target proteins is proposed to act as a metabolic sensor that links glucose metabolism to neuronal function. In a process that resembles phosphorylation [15], O-GlcNAc, derived from the final product of the nutrient-dependent hexosamine biosynthetic pathway (HBP), is added to or removed from hydroxyl groups of serine and/or threonine residues by two highly conserved intracellular enzymes, O-GlcNAc transferase (OGT) and O-linked-β-N-acetylglucosaminidase (OGA), respectively [16,17]. Recent breakthroughs revealed that the forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, accumulation of protein KRN 7000 chemicals and memory deficits [18]. Moreover, amyloid precursor protein (APP) and tau protein, as well as several proteins involved in regulatory cascades that mediate intracellular signaling, were shown to be heavily modified by O-GlcNAc [19]. During synaptic activity O-GlcNAcylation also regulates mitochondrial trafficking by targeting the mitochondrial motor-adaptor Milton, which is responsible for tethering mitochondria to motor proteins allowing the movement of these organelles along the KRN 7000 chemicals microtubule tracks [20]. However, so far, there is no consensus regarding the exact participation of O-GlcNAcylation in AD with conflicting data reporting both augmented and diminished O-GlcNAcylation levels in this neurodegenerative disease. Furthermore, the exact mechanism responsible for altered O-GlcNAcylation in AD brain remains inconclusive. Taking into account that AD-related glucose hypometabolism is accompanied by an abnormal mitochondrial function and distribution within neurons, which ultimately culminates in synaptic “starvation” and neuronal degeneration, and that O-GlcNAcylation was shown to modulate mitochondrial function, motility and distribution, the present study was undertaken to clarify the involvement O-GlcNAcylation in AD mitochondrial pathology.
    Materials and methods
    Results
    Discussion The present study shows reduced levels of O-GlcNAcylation in several models of AD. Notably, a strong correlation was established between global O-GlcNAcylation levels and some AD-associated pathological features, including hampered mitochondrial bioenergetic function and altered mitochondrial morphology and distribution. Importantly, the pharmacological increase in O-GlcNAcylation levels by Thiamet-G, which inhibits OGA, averted the loss of O-GlcNAcylation levels and cell viability in in vitro models of the disease, reinforcing the idea that targeting this posttranslational modification may constitute a feasible therapeutic intervention to tackle AD pathology. Faulty cerebral glucose metabolism has been pinpointed as a contributing factor underlying the neurodegenerative events that occur in AD [31]. PET studies using 2-fluoro-2-deoxy-glucopyranose (FDG) showed a progressive decline in cerebral glucose metabolism in AD [32,33]. Of note, lessons from clinical and experimental studies revealed that the decline in brain glucose uptake and metabolism occurs decades before the onset of AD symptoms and histopathological changes suggesting that metabolic deficits occur early in the course of AD [34]. Using post-mortem human brain tissue, we observed a reduction of global O-GlcNAcylation levels in brain tissue from AD subjects, this reduction being more pronounced in brain cortex (Fig. 1), which is in accordance with the observations made by Liu and collaborators [35]. As a plausible explanation, these authors attributed the reduction in O-GlcNAcylation to reduced neuronal glucose availability due to down-regulation of glucose transporters (GLUT) 1 and GLUT3 in the AD brain [36]. A recent study shows that the activation of calpain 1 causes GLUT3 proteolysis and downregulation of O-GlcNAcylation in AD brains [34]. In contrast, Förster and collaborators detected augmented cytosolic O-GlcNAc levels in brain tissue from AD subjects [37]. Those conflicting observations may be the result of the analyses of different post mortem brain tissue regions at different stages of the disease conjugated with different analysis methods as well as the use of different anti-O-GlcNAc antibodies. Furthermore, O-GlcNAcylation levels fluctuate depending on the post mortem interval [38] and stage of the disease.