title: Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging.
abstract: Low-complexity "prion-like" domains in key RNA-binding proteins (RBPs) mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age in C. elegans and that reduced insulin/insulin-like growth factor 1 (IGF-1) daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress-granule-related RBP aggregates are associated with reduced fitness. We show that heat shock transcription factor 1 (HSF-1) is a main regulator of stress-granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress-granule-related RBPs, partly by decreasing the buildup of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases.
authors.affiliation: German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany; Graduate Training Centre of Neuroscience, 72074 Tübingen, Germany.
authors.forename: Marie C
authors.initials: MC
authors.lastname: Lechler
authors.affiliation: German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
authors.forename: Emily D
authors.initials: ED
authors.lastname: Crawford
authors.affiliation: German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany; Graduate Training Centre of Neuroscience, 72074 Tübingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Groh
authors.affiliation: German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Widmaier
authors.affiliation: German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany.
authors.forename: Raimund
authors.initials: R
authors.lastname: Jung
authors.affiliation: Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin, 13125 Berlin, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Kirstein
authors.affiliation: Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trinidad
authors.affiliation: Mass Spectrometry Facility, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.affiliation: German Center for Neurodegenerative Diseases, 72076 Tübingen, Germany. Electronic address: della.david@dzne.de.
authors.forename: Della C
authors.initials: DC
authors.lastname: David
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008136:Longevity; D009154:Mutation / Q000235:genetics; D066329:Protein Aggregates; D012313:RNA / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility
chemical_list: D029742:Caenorhabditis elegans Proteins; D006360:Heat-Shock Proteins; D007328:Insulin; D066329:Protein Aggregates; D016601:RNA-Binding Proteins; D012313:RNA; D007334:Insulin-Like Growth Factor I; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin
keywords: Caenorhabditis elegans; DAF-2; HSF-1; RNA-binding proteins; aging; longevity; neurodegenerative diseases; protein aggregation; stress granules