Glucose effects on polyglutamine-induced proteotoxic stress in Caenorhabditis elegans

Abstract Many age-related diseases (ARDs) including virtually all neurodegenerative diseases (NDs) are characterized by the accumulation of proteins that are thought to significantly contribute to disease pathogenesis. One of the cell’s primary systems for the degradation of misfolded/damaged proteins is the Ubiquitin Proteasome System (UPS), and its impairment is implicated in essentially all NDs. Thus, upregulating this system to combat NDs has garnered a great deal of interest in recent years. Various animal models have focused on increasing the total proteasome levels, but thus far, none have focused on intrinsic activation of the proteasome itself. With this in mind, we constructed a, first to our knowledge, animal model that endogenously expresses a hyperactive open-gate proteasome in Caenorhabditis elegans (C. elegans). The gate-destabilizing mutation introduced into the nematode germline created a viable nematode population with substantially enhanced proteasomal peptidase and unstructured protein degradation activity. These CRISPR edited nematodes showed a significantly increased lifespan and substantial resistance to oxidative/proteotoxic stress with surprisingly mild consequential phenotypes. These results show that introducing a constitutively active proteasome into a multicellular organism is feasible and suggests targeting the proteasome gating mechanism as a valid approach for future ARD research efforts in mammals.

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Inhibition of polyglutamine-mediated proteotoxicity by Astragalus membranaceus polysaccharide through the DAF-16/FOXO transcription factor in Caenorhabditis elegans

Biochemical Journal ◽

10.1042/bj20110621 ◽

2011 ◽

Vol 441 (1) ◽

pp. 417-424 ◽

Cited By ~ 47

Author(s):

Hanrui Zhang ◽

Ni Pan ◽

Siqin Xiong ◽

Shenglong Zou ◽

Haifeng Li ◽

...

Keyword(s):

Transcription Factor ◽

Caenorhabditis Elegans ◽

Late Onset ◽

Late Embryogenesis Abundant ◽

Astragalus Membranaceus ◽

Adult Lifespan ◽

Proteotoxic Stress ◽

Dauer Formation ◽

Polyglutamine Aggregation ◽

Lifespan Regulation

Late-onset neurodegenerative diseases are characterized by progressive accumulation of aggregation-prone proteins and global disruption of the proteostasis network, e.g. abnormal polyQ (polyglutamine) aggregation in Huntington's disease. Astragalus membranaceus polysaccharide (astragalan) has recently been shown to modulate aging and proteotoxic stress pathways. Using Caenorhabditis elegans models, we now show that astragalan not only reduces polyQ aggregation, but also alleviates the associated neurotoxicity. We also reveal that astragalan can extend the adult lifespan of wild-type and polyQ nematodes, indicating a connection of its anti-aging benefit with the toxicity-suppressing effect. Further examination demonstrates that astragalan can extend the lifespan of daf-2 and age-1, but not daf-16, mutant nematodes of the insulin-like aging and stress pathway, suggesting a lifespan-regulation signalling independent of DAF (abnormal dauer formation)-2/IGF-1R (insulin-like growth factor 1 receptor), but dependent on the DAF-16/FOXO (forkhead box O) transcription factor, a pivotal integrator of divergent signalling pathways related to both lifespan regulation and stress resistance. We also show that a subset of DAF-16 downstream genes are regulated by astragalan, including the DAF-16 transcriptional target gene scl-20, which is itself constitutively up-regulated in transgenic polyQ nematodes. These findings, together with our previous work on LEA (late embryogenesis abundant) proteins and trehalose, provide a revealing insight into the potential of stress and lifespan regulators in the prevention of proteotoxic disorders.

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Review for "The connectome of the Caenorhabditis elegans pharynx"

10.1002/cne.24932/v1/review1 ◽

2020 ◽

Author(s):

Sreekanth Chalasani

Keyword(s):

Caenorhabditis Elegans

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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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