title: Inhibition of polyglutamine-mediated proteotoxicity by Astragalus membranaceus polysaccharide through the DAF-16/FOXO transcription factor in Caenorhabditis elegans.
abstract: 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.
authors: Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
authors: Hanrui
authors: H
authors: Zhang
authors: Ni
authors: N
authors: Pan
authors: Siqin
authors: S
authors: Xiong
authors: Shenglong
authors: S
authors: Zou
authors: Haifeng
authors: H
authors: Li
authors: Lingyun
authors: L
authors: Xiao
authors: Zhijian
authors: Z
authors: Cao
authors: Alan
authors: A
authors: Tunnacliffe
authors: Zebo
authors: Z
authors: Huang
mesh_terms: D000818:Animals; D027885:Astragalus propinquus / Q000737:chemistry*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D004721:Endoplasmic Reticulum; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D010455:Peptides / Q000378:metabolism*; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D010455:Peptides; D011134:Polysaccharides; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C097188:polyglutamine