title: Daf-2 signaling modifies mutant SOD1 toxicity in C. elegans.
abstract: The DAF-2 Insulin/IGF-1 signaling (IIS) pathway is a strong modifier of Caenorhabditis elegans longevity and healthspan. As aging is the greatest risk factor for developing neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), we were interested in determining if DAF-2 signaling modifies disease pathology in mutant superoxide dismutase 1 (SOD1) expressing C. elegans. Worms with pan-neuronal G85R SOD1 expression demonstrate significantly impaired locomotion as compared to WT SOD1 expressing controls and they develop insoluble SOD1 aggregates. Reductions in DAF-2 signaling, either through a hypomorphic allele or neuronally targeted RNAi, decreases the abundance of aggregated SOD1 and results in improved locomotion in a DAF-16 dependant manner. These results suggest that manipulation of the DAF-2 Insulin/IGF-1 signaling pathway may have therapeutic potential for the treatment of ALS.
authors.affiliation: Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, United States of America. boccitto@mail.med.upenn.edu
authors.forename: Marco
authors.initials: M
authors.lastname: Boccitto
authors.forename: Todd
authors.initials: T
authors.lastname: Lamitina
authors.forename: Robert G
authors.initials: RG
authors.lastname: Kalb
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D008124:Locomotion; D034622:RNA Interference; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000072105:Superoxide Dismutase-1
chemical_list: D029742:Caenorhabditis elegans Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin