Publicação

Neuron-specific proteotoxicity of mutant ataxin-3 in C. elegans: rescue by the DAF-16 and HSF-1 pathways

Detalhes bibliográficos
Resumo:	The risk of developing neurodegenerative diseases increases with age. Although many of the molecular pathways regulating proteotoxic stress and longevity are well characterized, their contribution to disease susceptibility remains unclear. In this study, we describe a new Caenorhabditis elegans model of Machado–Joseph disease pathogenesis. Pan-neuronal expression of mutant ATXN3 leads to a polyQ-length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Analysis of different neurons revealed a pattern of dorsal nerve cord and sensory neuron susceptibility to mutant ataxin-3 that was distinct from the aggregation and toxicity profiles of polyQ-alone proteins. This reveals that the sequences flanking the polyQ-stretch in ATXN3 have a dominant influence on cell-intrinsic neuronal factors that modulate polyQ-mediated athogenesis. Aging influences the ATXN3 phenotypes which can be suppressed by the nregulation of the insulin/insulin growth factor-1-like signaling pathway and activation of heat shock factor-1.
Autores principais:	Castro, Andreia Cristiana Teixeira de
Outros Autores:	Ailion, Michael; Jalles, Ana; Brignull, Heather; Vilaça, João L.; Dias, N. S.; Rodrigues, Pedro L.; Oliveira, João F.; Neves-Carvalho, Andreia; Morimoto, Richard; Maciel, P.
Ano:	2011
País:	Portugal
Tipo de documento:	artigo
Tipo de acesso:	acesso aberto
Instituição associada:	Universidade do Minho
Idioma:	inglês
Origem:	RepositóriUM - Universidade do Minho

Descrição
Resumo:	The risk of developing neurodegenerative diseases increases with age. Although many of the molecular pathways regulating proteotoxic stress and longevity are well characterized, their contribution to disease susceptibility remains unclear. In this study, we describe a new Caenorhabditis elegans model of Machado–Joseph disease pathogenesis. Pan-neuronal expression of mutant ATXN3 leads to a polyQ-length dependent, neuron subtype-specific aggregation and neuronal dysfunction. Analysis of different neurons revealed a pattern of dorsal nerve cord and sensory neuron susceptibility to mutant ataxin-3 that was distinct from the aggregation and toxicity profiles of polyQ-alone proteins. This reveals that the sequences flanking the polyQ-stretch in ATXN3 have a dominant influence on cell-intrinsic neuronal factors that modulate polyQ-mediated athogenesis. Aging influences the ATXN3 phenotypes which can be suppressed by the nregulation of the insulin/insulin growth factor-1-like signaling pathway and activation of heat shock factor-1.