Prediction of human tau 3D structure, and interplay between O-β-GlcNAc and phosphorylation modifications in Alzheimer’s disease: C. elegans as a suitable model to study these interactions in vivo

Ahmad, Waqar; Shabbiri, Khadija; Ahmad, Ishtiaq

doi:10.1016/j.bbrc.2020.05.176

Cited by 5 publications

(3 citation statements)

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“…C. elegans is well-suited for such studies as it has been used extensively to study the metabolic profiling and overlapping, genetics of aging and associated age-related diseases such as AD. 35 , 36 , 37 A decrease in Aβ mediated pathology in response to suppression of dld-1 supports the notion that decreased energy metabolism is neuroprotective.…”

Section: Introductionsupporting

confidence: 61%

Suppression of a core metabolic enzyme dihydrolipoamide dehydrogenase (dld) protects against amyloid beta toxicity in C. elegans model of Alzheimer's disease

Ahmad

Ebert

2021

Genes & Diseases

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A decrease in energy metabolism is associated with Alzheimer's disease (AD), but it is not known whether the observed decrease exacerbates or protects against the disease. The importance of energy metabolism in AD is reinforced by the observation that variants of dihydrolipoamide dehydrogenase (DLD), is genetically linked to late-onset AD. To determine whether DLD is a suitable therapeutic target, we suppressed the dld-1 gene in Caenorhabditis elegans that express human Aβ peptide in either muscles or neurons. Suppression of the dld-1 gene resulted in significant restoration of vitality and function that had been degraded by Aβ pathology. This included protection of neurons and muscles cells. The observed decrease in proteotoxicity was associated with a decrease in the formation of toxic oligomers rather than a decrease in the abundance of the Aβ peptide. The mitochondrial uncoupler, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), which like dld-1 gene expression inhibits ATP synthesis, had no significant effect on Aβ toxicity. Proteomics data analysis revealed that beneficial effects after dld-1 suppression could be due to change in energy metabolism and activation of the pathways associated with proteasomal degradation, improved cell signaling and longevity. Thus, some features unique to dld-1 gene suppression are responsible for the therapeutic benefit. By direct genetic intervention, we have shown that acute inhibition of dld-1 gene function may be therapeutically beneficial. This result supports the hypothesis that lowering energy metabolism protects against Aβ pathogenicity and that DLD warrants further investigation as a therapeutic target.

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Section: Introductionsupporting

confidence: 61%

Suppression of a core metabolic enzyme dihydrolipoamide dehydrogenase (dld) protects against amyloid beta toxicity in C. elegans model of Alzheimer's disease

Ahmad

Ebert

2021

Genes & Diseases

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“…The enzymes responsible for O-linked N-acetylglucosamine (O-GlcNAc) cycling (OGT-1 and OGA-1 in C. elegans ) play an important role in controlling cytoplasmic and nuclear proteostasis [ 151 ], and show high homology to human orthologues [ 152 ]. Mutants of these enzymes alter the toxicity of Aβ and mutant tau in C. elegans models [ 153 ], so it has been proposed to use these models to search for small-molecule modulators of O-GlcNAc metabolism that may influence neurodegeneration.…”

Section: Use Of C Elegans Models Of Alzheimer’s Di...mentioning

confidence: 99%

Modeling Alzheimer’s Disease in Caenorhabditis elegans

et al. 2022

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Alzheimer’s disease (AD) is the most frequent cause of dementia. After decades of research, we know the importance of the accumulation of protein aggregates such as β-amyloid peptide and phosphorylated tau. We also know that mutations in certain proteins generate early-onset Alzheimer’s disease (EOAD), and many other genes modulate the disease in its sporadic form. However, the precise molecular mechanisms underlying AD pathology are still unclear. Because of ethical limitations, we need to use animal models to investigate these processes. The nematode Caenorhabditis elegans has received considerable attention in the last 25 years, since the first AD models overexpressing Aβ peptide were described. We review here the main results obtained using this model to study AD. We include works studying the basic molecular mechanisms of the disease, as well as those searching for new therapeutic targets. Although this model also has important limitations, the ability of this nematode to generate knock-out or overexpression models of any gene, single or combined, and to carry out toxicity, recovery or survival studies in short timeframes with many individuals and at low cost is difficult to overcome. We can predict that its use as a model for various diseases will certainly continue to increase.

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“…Another substance, chicoric acid (CA), has also been shown to regulate glucose metabolism by increasing GluT1, promoting the glycosylation of tau proteins, thereby reducing their phosphorylation levels and preventing or improving AD symptoms [ 58 ]. Recently, a three-dimensional structural model of tau predicted by ab-initio modeling provided 25 potential sites for tau O-GlcNAc glycosylation, which may be a target and reference for AD drug development [ 59 ]. Some proteins whose glycosylation patterns are significantly altered in AD, such as APP, β-secretase, and tau proteins, also have considerable potential as therapeutic targets for AD for the same reason.…”

Section: Introductionmentioning

confidence: 99%

New insight into protein glycosylation in the development of Alzheimer’s disease

Zhao,

Lang

2023

Cell Death Discov.

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Alzheimer’s disease (AD) is a chronic neurodegenerative disease that seriously endangers the physical and mental health of patients, however, there are still no effective drugs or methods to cure this disease up to now. Protein glycosylation is the most common modifications of the translated proteins in eukaryotic cells. Recently many researches disclosed that aberrant glycosylation happens in some important AD-related proteins, such as APP, Tau, Reelin and CRMP-2, etc, suggesting a close link between abnormal protein glycosylation and AD. Because of its complexity and diversity, glycosylation is thus considered a completely new entry point for understanding the precise cause of AD. This review comprehensively summarized the currently discovered changes in protein glycosylation patterns in AD, and especially introduced the latest progress on the mechanism of protein glycosylation affecting the progression of AD and the potential application of protein glycosylation in AD detection and treatment, thereby providing a wide range of opportunities for uncovering the pathogenesis of AD and promoting the translation of glycosylation research into future clinical applications.

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Prediction of human tau 3D structure, and interplay between O-β-GlcNAc and phosphorylation modifications in Alzheimer’s disease: C. elegans as a suitable model to study these interactions in vivo

Cited by 5 publications

References 53 publications

Suppression of a core metabolic enzyme dihydrolipoamide dehydrogenase (dld) protects against amyloid beta toxicity in C. elegans model of Alzheimer's disease

Suppression of a core metabolic enzyme dihydrolipoamide dehydrogenase (dld) protects against amyloid beta toxicity in C. elegans model of Alzheimer's disease

Modeling Alzheimer’s Disease in Caenorhabditis elegans

New insight into protein glycosylation in the development of Alzheimer’s disease

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