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

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101596414 Publication Model: Electronic Cited Medium: Internet ISSN: 2218-273X (Electronic) Linking ISSN: 2218273X NLM ISO Abbreviation: Biomolecules Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, 2011-

Caenorhabditis elegans*/drug effects ; Caenorhabditis elegans*/metabolism ; Caenorhabditis elegans*/genetics ; Amyloid beta-Peptides*/metabolism ; Amyloid beta-Peptides*/genetics ; Peptides*/pharmacology ; 3-Hydroxyanthranilic Acid*/metabolism ; Paralysis*/chemically induced ; Paralysis*/metabolism ; Paralysis*/genetics; Animals ; Disease Models, Animal ; Alzheimer Disease/metabolism ; Alzheimer Disease/genetics ; Alzheimer Disease/drug therapy ; Caenorhabditis elegans Proteins/metabolism ; Caenorhabditis elegans Proteins/genetics ; Huntington Disease/metabolism ; Huntington Disease/genetics ; Dioxygenases/metabolism ; Dioxygenases/genetics

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.

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2P30AG038070-06A2 United States NH NIH HHS; 1R35GM133588-01A1 United States NH NIH HHS

Keywords: Alzheimer’s disease; Caenorhabditis elegans; Huntington’s disease; kynurenine; metabolism; neurodegeneration; proteotoxicity; tryptophan

26700-71-0 (polyglutamine)
0 (Amyloid beta-Peptides)
0 (Peptides)
1UQB1BT4OT (3-Hydroxyanthranilic Acid)
0 (Caenorhabditis elegans Proteins)
EC 1.13.11.- (Dioxygenases)

Date Created: 20240524 Date Completed: 20240524 Latest Revision: 20240526

20240526

PMC11117628

10.3390/biom14050599

38786006