12 Alterations in protein folding may lead to aggregation of misfolded proteins, which is strongly 13 correlated with neurotoxicity and cell death. Protein aggregation has been shown as a normal 14 consequence of aging, but it is largely associated with age-related disease, particularly 15 neurodegenerative diseases like Huntington disease (HD). Huntington disease is caused by a CAG 16 repeat expansion in the huntingtin gene and serves as a useful model for neurodegeneration due to its 17 strictly genetic origin. Research in the model organism Caenorhabditis elegans suggests that glucose 18 protects against cell stress, including proteotoxicity related to aggregation, despite the well-known, 19 lifespan-shortening effects of glucose. We hypothesized that glucose could be beneficial by 20 alleviating energy deficiency, a well-characterized phenomenon in HD, or by upregulating stress 21 resistance pathways. We used C. elegans expressing polyglutamine repeats to quantify lifespan, 22 motility, reproduction, learning, and activity of succinate dehydrogenase (SDH), with and without 23 glucose, to identify the role of glucose in proteotoxicity and neuroprotection. Our data show HD 24 worms on glucose plates exhibited shorter lifespans, no change in motility, learning, or SDH product 25 formation, but had altered reproductive phenotypes similar to dietary restriction. Additionally, worms 26 expressing toxic polyglutamine repeats were unable to learn association of food with a neutral 27 odorant. We also observed tissue-specific differences; polyglutamine appeared to be slightly more 28 toxic to muscle cells than neurons. Rather than increasing energy production, glucose appeared to 29 decrease mitochondrial metabolism, as SDH formation decreases with added glucose. Future work 30 investigating glucose-mediated neuroprotection should focus on connecting metabolism, sirtuin 31 activation, and DAF-16 activation. 32 Glucose Impacts Polyglutamine Phenotypes 3 33 Introduction 34 Protein aggregates are a shared phenotype of many fatal neurodegenerative diseases including 35 polyglutamine disorders such as Huntington disease (HD) [1]. The exact nature of cytotoxicity and 36 neuronal death in HD and other neurodegenerative diseases is currently unknown, but many 37 hypotheses have been proposed, including: loss-of-function and/or gain-of-function mutations, 38 excitotoxicity, oxidative stress, aberrant gene expression, and apoptosis [2-5]. HD provides a 39 convenient model for neurodegeneration research, as it is strictly a genetic disease caused by a 40 specific mutation: a CAG trinucleotide repeat expansion in the gene encoding the huntingtin protein 41 (HTT) [6]. HTT is expressed ubiquitously, though most abundantly in neurons, and is found within 42 the nucleus and cytoplasm of the cell. Similarly, HD-afflicted neurons exhibit intranuclear and 43 cytosolic aggregates containing mutant HTT, ubiquitin, and other proteins [7]. What role these 44 aggregates play in neurotoxicity is unclear, with competing hypotheses of deleterio...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.