The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans
06 Aug 2002-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 99, Iss: 16, pp 10417-10422
TL;DR: Experimental support is provided for the threshold hypothesis of polyQ-mediated toxicity in an experimental organism and the importance of the threshold as a point at which genetic modifiers and aging influence biochemical environment and protein homeostasis in the cell is emphasized.
Abstract: Studies of the mutant gene in Huntington's disease, and for eight related neurodegenerative disorders, have identified polyglutamine (polyQ) expansions as a basis for cellular toxicity. This finding has led to a disease hypothesis that protein aggregation and cellular dysfunction can occur at a threshold of approximately 40 glutamine residues. Here, we test this hypothesis by expression of fluorescently tagged polyQ proteins (Q29, Q33, Q35, Q40, and Q44) in the body wall muscle cells of Caenorhabditis elegans and show that young adults exhibit a sharp boundary at 35-40 glutamines associated with the appearance of protein aggregates and loss of motility. Surprisingly, genetically identical animals expressing near-threshold polyQ repeats exhibited a high degree of variation in the appearance of protein aggregates and cellular toxicity that was dependent on repeat length and exacerbated during aging. The role of genetically determined aging pathways in the progression of age-dependent polyQ-mediated aggregation and cellular toxicity was tested by expressing Q82 in the background of age-1 mutant animals that exhibit an extended lifespan. We observed a dramatic delay of polyQ toxicity and appearance of protein aggregates. These data provide experimental support for the threshold hypothesis of polyQ-mediated toxicity in an experimental organism and emphasize the importance of the threshold as a point at which genetic modifiers and aging influence biochemical environment and protein homeostasis in the cell.
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TL;DR: The proteostasis network is described, a set of interacting activities that maintain the health of proteome and the organism that has the potential to ameliorate some of the most challenging diseases of this era.
Abstract: The protein components of eukaryotic cells face acute and chronic challenges to their integrity. Eukaryotic protein homeostasis, or proteostasis, enables healthy cell and organismal development and aging and protects against disease. Here, we describe the proteostasis network, a set of interacting activities that maintain the health of proteome and the organism. Deficiencies in proteostasis lead to many metabolic, oncological, neurodegenerative, and cardiovascular disorders. Small-molecule or biological proteostasis regulators that manipulate the concentration, conformation, quaternary structure, and/or the location of protein(s) have the potential to ameliorate some of the most challenging diseases of our era.
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TL;DR: The findings suggest that HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity, which couple the normal aging process to this type of age-related disease.
Abstract: The Caenorhabditis elegans transcription factor HSF-1, which regulates the heat-shock response, also influences aging. Reducing hsf-1 activity accelerates tissue aging and shortens life-span, and we show that hsf-1 overexpression extends lifespan. We find that HSF-1, like the transcription factor DAF-16, is required for daf-2–insulin/IGF-1 receptor mutations to extend life-span. Our findings suggest this is because HSF-1 and DAF-16 together activate expression of specific genes, including genes encoding small heat-shock proteins, which in turn promote longevity. The small heat-shock proteins also delay the onset of polyglutamine-expansion protein aggregation, suggesting that these proteins couple the normal aging process to this type of age-related disease.
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TL;DR: Mutations in genes affecting endocrine signaling, stress responses, metabolism, and telomeres can all increase the life spans of model organisms, leading to a mechanistic understanding of how these two processes--aging and disease susceptibility--are linked.
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TL;DR: Recent findings demonstrating the role of mammalian sirtuins as regulators of physiology, calorie restriction, and aging sharpen the understanding of sirtUins as potential pharmacological targets to treat the major diseases of aging.
Abstract: Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, worms and flies. Mammals contain seven homologs of yeast Sir2, SIRT1-7. Here, we review recent findings demonstrating the role of these mammalian sirtuins as regulators of physiology, calorie restriction, and aging. The current findings sharpen our understanding of sirtuins as potential pharmacological targets to treat the major diseases of aging.
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Cites background from "The threshold for polyglutamine-exp..."
...One study shows that neurotoxicity in worms is spared by the age-1 mutation, which reduces insulin-like signaling (Morley et al. 2002), or in a transgenic strain overexpressing sir-2....
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TL;DR: This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation.
Abstract: The biological functions of proteins are governed by their three-dimensional fold. Protein folding, maintenance of proteome integrity, and protein homeostasis (proteostasis) critically depend on a complex network of molecular chaperones. Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases. In the cytosol, different classes of molecular chaperones cooperate in evolutionarily conserved folding pathways. Nascent polypeptides interact cotranslationally with a first set of chaperones, including trigger factor and the Hsp70 system, which prevent premature (mis)folding. Folding occurs upon controlled release of newly synthesized proteins from these factors or after transfer to downstream chaperones such as the chaperonins. Chaperonins are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation.
1,249 citations
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