Glucose availability impacts proteotoxic stress in Caenorhabditis elegans
Alterations in protein folding may lead to aggregation of misfolded proteins, which is strongly correlated with neurotoxicity and cell death. Protein aggregation has been shown as a normal consequence of aging, but it is largely associated with age-related disease, particularly neurodegenerative diseases like Huntington disease (HD). Huntington disease is caused by a CAG repeat expansion in the huntingtin gene and serves as a useful model for neurodegeneration due to its strictly genetic origin. Research in the model organism Caenorhabditis elegans suggests that glucose protects against cell stress, including proteotoxicity related to aggregation, despite the well-known, lifespan-shortening effects of glucose. We hypothesized that glucose could be beneficial by alleviating energy deficiency, a well-characterized phenomenon in HD, or by upregulating stress resistance pathways. We used C. elegans expressing polyglutamine repeats to quantify lifespan, motility, reproduction, learning, and activity of succinate dehydrogenase (SDH), with and without glucose, to identify the role of glucose in proteotoxicity and neuroprotection. Our data show HD worms on glucose plates exhibited shorter lifespans, no change in motility, learning, or SDH product formation, but had altered reproductive phenotypes similar to dietary restriction. Additionally, worms expressing toxic polyglutamine repeats were unable to learn association of food with a neutral odorant. We also observed tissue-specific differences; polyglutamine appeared to be slightly more toxic to muscle cells than neurons. Rather than increasing energy production, glucose appeared to decrease mitochondrial metabolism, as SDH formation decreases with added glucose. Future work investigating glucose-mediated neuroprotection should focus on connecting metabolism, sirtuin activation, and DAF-16 activation.