Journal Article

Chronic high-sugar diet in adulthood protects Caenorhabditis elegans from 6-OHDA-induced dopaminergic neurodegeneration

Heffernan, Nathan, Ryde, Ian T., Hartman, Jessica H., Meng, Lingfeng, Morton, Katherine S., Sherwood, David R., Kenny-Ganzert, Isabel W., Meyer, Joel N.

2023

Overview

Background Diets high in saturated fat and sugar, termed “Western diets,” have been associated with several negative health outcomes, including increased risk for neurodegenerative disease. Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and is characterized by the progressive death of dopaminergic neurons in the brain. We build upon previous work characterizing the impact of high-sugar diets in Caenorhabditis elegans to mechanistically evaluate the relationship between high-sugar diets and dopaminergic neurodegeneration. Results Adult high-glucose and high-fructose diets, or exposure from day 1 to 5 of adulthood, led to increased lipid content, shorter lifespan, and decreased reproduction. However, in contrast to previous reports, we found that adult chronic high-glucose and high-fructose diets did not induce dopaminergic neurodegeneration alone and were protective from 6-hydroxydopamine (6-OHDA) induced degeneration. Neither sugar altered baseline electron transport chain function and both increased vulnerability to organism-wide ATP depletion when the electron transport chain was inhibited, arguing against energetic rescue as a basis for neuroprotection. The induction of oxidative stress by 6-OHDA is hypothesized to contribute to its pathology, and high-sugar diets prevented this increase in the soma of the dopaminergic neurons. However, we did not find increased expression of antioxidant enzymes or glutathione levels. Instead, we found evidence suggesting downregulation of the dopamine reuptake transporter dat-1 that could result in decreased 6-OHDA uptake. Conclusions Our work uncovers a neuroprotective role for high-sugar diets, despite concomitant decreases in lifespan and reproduction. Our results support the broader finding that ATP depletion alone is insufficient to induce dopaminergic neurodegeneration, whereas increased neuronal oxidative stress may drive degeneration. Finally, our work highlights the importance of evaluating lifestyle by toxicant interactions.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 6-Hydroxydopamine / Adenosine Triphosphate - metabolism / Adults / Animals / Antioxidants / Biomedical and Life Sciences / C. elegans / Caenorhabditis elegans / Caenorhabditis elegans - metabolism / Corn syrup / Degeneration / Depletion / Dextrose / Diet / Disease / Disease Models, Animal / Dopamine / Dopamine - metabolism / Dopamine receptors / Dopamine transporter / Dopaminergic Neurons - physiology / Electron transport / Electron transport chain / Enzymes / Food habits / Fructose / Fructose - adverse effects / Fructose - metabolism / Glucose / Glucose - metabolism / Glutathione / Health aspects / Health risks / High fat diet / Humans / Insulin resistance / Life Sciences / Life span / Lipids / Morphology / Movement disorders / Nematodes / Nerve Degeneration - chemically induced / Nerve Degeneration - metabolism / Nerve Degeneration - prevention & control / Nervous system diseases / Neurodegeneration / Neurodegenerative diseases / Neurodegenerative Diseases - chemically induced / Neurodegenerative Diseases - metabolism / Neurons / Neuroprotection / Obesity / Oxidative stress / Oxidopamine - adverse effects / Oxidopamine - metabolism / Parkinson's disease / Research Article / Sugar / Sugars - adverse effects / Sugars - metabolism / Toxicants / Type 2 diabetes / Worms