TDP‐43 promotes pathological tau phosphorylation and selective neurotoxicity in
            C. elegans

AbstractThe microtubule associated tau protein becomes hyperphosphorylated in Alzheimer’s disease (AD). While hyperphosphorylation promotes neurodegeneration, the cause and consequences of this abnormal modification are poorly understood. As impaired energy metabolism is an important hallmark of AD progression, we tested whether it could trigger phosphorylation of human tau protein in a transgenic C. elegans model of AD. We found that inhibition of a mitochondrial enzyme of energy metabolism, dihydrolipoamide dehydrogenase (DLD) resulted in elevated whole-body glucose levels as well as increased phosphorylation of tau. Hyperglycemia and tau phosphorylation were induced by either epigenetic suppression of the dld-1 gene or by inhibition of the DLD enzyme by the inhibitor, 2-methoxyindole-2-carboxylic acid (MICA). Although the calcium ionophore A23187 could reduce tau phosphorylation induced by either chemical or genetic suppression of DLD, it was unable to reduce tau phosphorylation induced by hyperglycemia. While inhibition of the dld-1 gene or treatment with MICA partially reversed the inhibition of acetylcholine neurotransmission by tau, neither treatment affected tau inhibited mobility. Conclusively, any abnormalities in energy metabolism were found to significantly affect the AD disease pathology.

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Glucose facilitates Aβ oligomerization and tau phosphorylation in C. elegans model of Alzheimer’s disease

10.1101/228437 ◽

2017 ◽

Author(s):

Waqar Ahmad

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glucose Metabolism ◽

Disease Progression ◽

Neurofibrillary Tangles ◽

Tau Phosphorylation ◽

Egg Laying ◽

Aβ Oligomers ◽

C Elegans ◽

Model Of Alzheimer’S Disease

AbstractFormation of Aβ plaques from peptide oligomers and development of neurofibrillary tangles from hyperphosphorylated tau are hallmarks of Alzheimer’s disease (AD). These markers of AD severity are further associated with impaired glucose metabolism. However, the exact role of glucose metabolism on disease progression has not been elucidated. In this study, the effects of glucose on Aβ and tau-mediated toxicity are investigated using a C. elegans model system. We find that addition of glucose or 2-deoxy-d-glucose (2DOG) to the growth medium delayed Aβ-associated paralysis, though it was unable to restore previously impaired acetylcholine neurotransmission in pre-existing Aβ-mediated pathology. Glucose also inhibited egg laying and hatching in the worms that express Aβ. The harmful effects of glucose were associated with an increase in toxic Aβ oligomers. Increased phosphorylation of tau is associated with formation of neurofibrillary tangles (NFTs) and increased severity of AD, but O-β-GlcNAcylation can inhibit phosphorylation of adjacent phosphorylation sites. We reasoned that high glucose levels might induce tau O-β-GlcNAcylation, thereby protecting against tau phosphorylation. Contrary to our expectation, glucose increased tau phosphorylation but not O-β-GlcNAcylation. Increasing O-β-GlcNAcylation, either with Thiamet-G (TMG) or by suppressing the O-GlcNAcase (oga-1) gene does interfere with and therefore reduce tau phosphorylation. Furthermore, reducing O-β-GlcNAcylation by suppressing O-GlcNAc transferase (ogt-1) gene causes an increase in tau phosphorylation. These results suggest that protective O-β-GlcNAcylation is not induced by glucose. Instead, as with vertebrates, we demonstrate that high levels of glucose exacerbate disease progression by promoting Aβ aggregation and tau hyperphosphorylation, resulting in disease symptoms of increased severity. The effects of glucose cannot be effectively managed by manipulating O-β-GlcNAcylation in the tau models of AD in C. elegans. Our observations suggest that glucose enrichment is unlikely to be an appropriate therapy to minimize AD progression.

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Dihydrolipoamide dehydrogenase suppression induces human tau phosphorylation by increasing whole body glucose levels in a C. elegans model of Alzheimer’s Disease

Experimental Brain Research ◽

10.1007/s00221-018-5341-0 ◽

2018 ◽

Vol 236 (11) ◽

pp. 2857-2866 ◽

Cited By ~ 5

Author(s):

Waqar Ahmad

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Tau Phosphorylation ◽

Whole Body ◽

Dihydrolipoamide Dehydrogenase ◽

C Elegans ◽

Glucose Levels ◽

Model Of Alzheimer’S Disease

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The glycomes of Caenorhabditis elegans and other model organisms

Biochemical Society Symposium ◽

10.1042/bss0690117 ◽

2002 ◽

Vol 69 ◽

pp. 117-134 ◽

Cited By ~ 47

Author(s):

Stuart M. Haslam ◽

David Gems ◽

Howard R. Morris ◽

Anne Dell

Keyword(s):

Caenorhabditis Elegans ◽

Current Knowledge ◽

Structural Data ◽

Model Organisms ◽

Entire Genome ◽

C Elegans ◽

The Face ◽

Area Of Concern ◽

Nematode Worm

There is no doubt that the immense amount of information that is being generated by the initial sequencing and secondary interrogation of various genomes will change the face of glycobiological research. However, a major area of concern is that detailed structural knowledge of the ultimate products of genes that are identified as being involved in glycoconjugate biosynthesis is still limited. This is illustrated clearly by the nematode worm Caenorhabditis elegans, which was the first multicellular organism to have its entire genome sequenced. To date, only limited structural data on the glycosylated molecules of this organism have been reported. Our laboratory is addressing this problem by performing detailed MS structural characterization of the N-linked glycans of C. elegans; high-mannose structures dominate, with only minor amounts of complex-type structures. Novel, highly fucosylated truncated structures are also present which are difucosylated on the proximal N-acetylglucosamine of the chitobiose core as well as containing unusual Fucα1–2Gal1–2Man as peripheral structures. The implications of these results in terms of the identification of ligands for genomically predicted lectins and potential glycosyltransferases are discussed in this chapter. Current knowledge on the glycomes of other model organisms such as Dictyostelium discoideum, Saccharomyces cerevisiae and Drosophila melanogaster is also discussed briefly.

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How do histone modifications contribute to transgenerational epigenetic inheritance in C. elegans?

Biochemical Society Transactions ◽

10.1042/bst20190944 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1019-1034 ◽

Cited By ~ 1

Author(s):

Rachel M. Woodhouse ◽

Alyson Ashe

Keyword(s):

Histone Modifications ◽

Molecular Mechanisms ◽

Epigenetic Inheritance ◽

Nematode Caenorhabditis Elegans ◽

Histone Methyltransferases ◽

Transgenerational Epigenetic Inheritance ◽

C Elegans ◽

Recent Developments ◽

Gene Regulatory

Gene regulatory information can be inherited between generations in a phenomenon termed transgenerational epigenetic inheritance (TEI). While examples of TEI in many animals accumulate, the nematode Caenorhabditis elegans has proven particularly useful in investigating the underlying molecular mechanisms of this phenomenon. In C. elegans and other animals, the modification of histone proteins has emerged as a potential carrier and effector of transgenerational epigenetic information. In this review, we explore the contribution of histone modifications to TEI in C. elegans. We describe the role of repressive histone marks, histone methyltransferases, and associated chromatin factors in heritable gene silencing, and discuss recent developments and unanswered questions in how these factors integrate with other known TEI mechanisms. We also review the transgenerational effects of the manipulation of histone modifications on germline health and longevity.

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Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

Biochemical Society Transactions ◽

10.1042/bst20200298 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1243-1253 ◽

Cited By ~ 1

Author(s):

Sukriti Kapoor ◽

Sachin Kotak

Keyword(s):

Symmetry Breaking ◽

Cell Fate ◽

Cell Cortex ◽

Axis Formation ◽

Aurora A Kinase ◽

Aurora A ◽

C Elegans ◽

Cell Embryo ◽

Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

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