Affiliation:
1. Universidade Federal de Santa Maria, Centro de Ciências Naturais e Exatas, Departamento de Bioquímica e Biologia Molecular, Programa de Pós-graduação em Ciências Biológicas: Bioquímica Toxicológica, Camobi, 97105-900, Santa Maria, RS, Brazil. Tel: +55-55-3220-9522
Abstract
Abstract
Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disease with a distinct phenotype. It occurs due to a mutation in the huntingtin (or IT19) gene with an abnormal CAG repeat, leading to a variable length N-terminal polyglutamine chain (poly-Q). Like most neurodegenerative diseases, HD is characterized by the abnormal deposition and aggregation of proteins in the cell, which impairs the proteostasis and disrupts cellular homeostasis. In this study, we used Caenorhabditis elegans as an animal model due to its easy genetic manipulation and high homology of genes and signaling pathways with mammals. Worms were exposed to diphenyl diselenide (PhSe)2 at 25, 50 and 100 μM, and then we analyzed the polyQ aggregation, neurodegeneration, touch response, reactive oxygen species (ROS) levels, lifespan and health span. In addition, we analyzed the involvement of the transcription factor DAF-16, a FOXO-ortholog, and the downstream heat-shock protein-16.2 (HSP-16.2) and superoxide dismutase-3 (SOD-3). Our data demonstrate that chronic treatment with (PhSe)2 reduced polyQ aggregation in muscle and polyQ mediated neuronal cell death of sensory neurons ASH, as well as maintaining the neuronal function. In addition, (PhSe)2 decreased ROS levels and extended the lifespan and health span of wild type and PolyQ mutant worms. The mechanism proposed is the activation of DAF-16, HSP-16.2 and SOD-3 in whole body tissues to increase the antioxidant capacity and regulation of proteostasis, decreasing PolyQ aggregation and toxicity and reducing ROS levels, leading to an increase in lifespan, and healthspan. Our findings provide new clues for treatment strategies for neurodegenerative diseases and other diseases caused by age-related protein aggregation.
Funder
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Ministério da Ciência e Tecnologia
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Universidade Federal de Santa Maria
Publisher
Oxford University Press (OUP)
Subject
Metals and Alloys,Biochemistry,Biomaterials,Biophysics,Chemistry (miscellaneous)
Cited by
9 articles.
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