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Biomolecules
Volume 14
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10.3390/biom14050599
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Article

3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity

by
Bradford T. Hull
1,
Kayla M. Miller
2,
Caroline Corban
3,
Grant Backer
3,
Susan Sheehan
3,
Ron Korstanje
3 and
George L. Sutphin
1,2,*
1
Molecular and Cellular Biology Department, University of Arizona, Tucson, AZ 85721, USA
2
Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85721, USA
3
The Jackson Laboratory, Bar Harbor, ME 04609, USA
*
Author to whom correspondence should be addressed.
Biomolecules 2024, 14(5), 599; https://doi.org/10.3390/biom14050599
Submission received: 1 May 2024 / Revised: 15 May 2024 / Accepted: 16 May 2024 / Published: 18 May 2024
(This article belongs to the Special Issue Molecular Advances in Mechanism and Regulation of Lifespan and Aging)
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Abstract

Age is the primary risk factor for neurodegenerative diseases such as Alzheimer’s and Huntington’s disease. Alzheimer’s disease is the most common form of dementia and a leading cause of death in the elderly population of the United States. No effective treatments for these diseases currently exist. Identifying effective treatments for Alzheimer’s, Huntington’s, and other neurodegenerative diseases is a major current focus of national scientific resources, and there is a critical need for novel therapeutic strategies. Here, we investigate the potential for targeting the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3HAA) using Caenorhabditis elegans expressing amyloid-beta or a polyglutamine peptide in body wall muscle, modeling the proteotoxicity in Alzheimer’s and Huntington’s disease, respectively. We show that knocking down the enzyme that degrades 3HAA, 3HAA dioxygenase (HAAO), delays the age-associated paralysis in both models. This effect on paralysis was independent of the protein aggregation in the polyglutamine model. We also show that the mechanism of protection against proteotoxicity from HAAO knockdown is mimicked by 3HAA supplementation, supporting elevated 3HAA as the mediating event linking HAAO knockdown to delayed paralysis. This work demonstrates the potential for 3HAA as a targeted therapeutic in neurodegenerative disease, though the mechanism is yet to be explored.
Keywords: metabolism; tryptophan; kynurenine; Alzheimer’s disease; Huntington’s disease; neurodegeneration; proteotoxicity; Caenorhabditis elegans metabolism; tryptophan; kynurenine; Alzheimer’s disease; Huntington’s disease; neurodegeneration; proteotoxicity; Caenorhabditis elegans

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MDPI and ACS Style

Hull, B.T.; Miller, K.M.; Corban, C.; Backer, G.; Sheehan, S.; Korstanje, R.; Sutphin, G.L. 3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity. Biomolecules 2024, 14, 599. https://doi.org/10.3390/biom14050599

AMA Style

Hull BT, Miller KM, Corban C, Backer G, Sheehan S, Korstanje R, Sutphin GL. 3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity. Biomolecules. 2024; 14(5):599. https://doi.org/10.3390/biom14050599

Chicago/Turabian Style

Hull, Bradford T., Kayla M. Miller, Caroline Corban, Grant Backer, Susan Sheehan, Ron Korstanje, and George L. Sutphin. 2024. "3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity" Biomolecules 14, no. 5: 599. https://doi.org/10.3390/biom14050599

APA Style

Hull, B. T., Miller, K. M., Corban, C., Backer, G., Sheehan, S., Korstanje, R., & Sutphin, G. L. (2024). 3-Hydroxyanthranilic Acid Delays Paralysis in Caenorhabditis elegans Models of Amyloid-Beta and Polyglutamine Proteotoxicity. Biomolecules, 14(5), 599. https://doi.org/10.3390/biom14050599

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