Journal ArticleDOI
Opposing Activities Protect Against Age-Onset Proteotoxicity
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TLDR
Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies, and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity.Abstract:
Aberrant protein aggregation is a common feature of late-onset neurodegenerative diseases, including Alzheimer9s disease, which is associated with the misassembly of the Aβ1-42 peptide. Aggregation-mediated Aβ1-42 toxicity was reduced in Caenorhabiditis elegans when aging was slowed by decreased insulin/insulin growth factor–1–like signaling (IIS). The downstream transcription factors, heat shock factor 1, and DAF-16 regulate opposing disaggregation and aggregation activities to promote cellular survival in response to constitutive toxic protein aggregation. Because the IIS pathway is central to the regulation of longevity and youthfulness in worms, flies, and mammals, these results suggest a mechanistic link between the aging process and aggregation-mediated proteotoxicity.read more
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Molecular chaperones in protein folding and proteostasis
TL;DR: It is suggested that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease, which may spring from a detailed understanding of the pathways underlying proteome maintenance.
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Adapting proteostasis for disease intervention.
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.
Journal ArticleDOI
Molecular Chaperone Functions in Protein Folding and Proteostasis
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.
Journal ArticleDOI
Neural mechanisms of ageing and cognitive decline
TL;DR: Advances in the biology of ageing in model organisms, together with molecular and systems-level studies of the brain, are beginning to shed light on these mechanisms and their potential roles in cognitive decline.
Journal ArticleDOI
Biological and Chemical Approaches to Diseases of Proteostasis Deficiency
TL;DR: It is proposed that small molecules can enhance proteostasis by binding to and stabilizing specific proteins (pharmacologic chaperones) or by increasing the protestasis network capacity (proteostasis regulators) and that such therapeutic strategies, including combination therapies, represent a new approach for treating a range of diverse human maladies.
References
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Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
Dominic M. Walsh,Igor Klyubin,Julia V. Fadeeva,William K. Cullen,Roger Anwyl,Michael S. Wolfe,Michael J. Rowan,Dennis J. Selkoe +7 more
TL;DR: It is reported that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.
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A C. elegans mutant that lives twice as long as wild type
TL;DR: Finding that mutations in the gene daf-2 can cause fertile, active, adult Caenorhabditis elegans hermaphrodites to live more than twice as long as wild type raises the possibility that the longevity of the dauer is not simply a consequence of its arrested growth, but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation.
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Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity
TL;DR: The identity of Alamar Blue is shown as resazurin, a very simple and versatile way of measuring cell proliferation and cytotoxicity that presents numerous advantages over other cytot toxicity or proliferation tests but there are several drawbacks to the routine use.
Journal ArticleDOI
A specific amyloid-|[beta]| protein assembly in the brain impairs memory
Sylvain Lesné,Ming Teng Koh,Linda Kotilinek,Rakez Kayed,Charles G. Glabe,Austin J. Yang,Michela Gallagher,Karen H. Ashe +7 more
TL;DR: It is found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which is proposed to be Aβ*56 (Aβ star 56), which may contribute to cognitive deficits associated with Alzheimer's disease.
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Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases.
Monica Bucciantini,Elisa Giannoni,Fabrizio Chiti,Fabrizio Chiti,Fabiana Baroni,Lucia Formigli,Jesús Zurdo,Niccolò Taddei,Giampietro Ramponi,Christopher M. Dobson,Massimo Stefani +10 more
TL;DR: This finding provides added evidence that avoidance of protein aggregation is crucial for the preservation of biological function and suggests common features in the origins of this family of protein deposition diseases.