title: Worming our way to novel drug discovery with the Caenorhabditis elegans proteostasis network, stress response and insulin-signaling pathways.
abstract: BACKGROUND
  Many human diseases result from a failure of a single protein to achieve the correct folding and tertiary conformation. These so-called 'conformational diseases' involve diverse proteins and distinctive cellular pathologies. They all engage the proteostasis network (PN), to varying degrees in an attempt to mange cellular stress and restore protein homeostasis. The insulin/insulin-like growth factor signaling (IIS) pathway is a master regulator of cellular stress response, which is implicated in regulating components of the PN.
  
  
  METHODS
  This review focuses on novel approaches to target conformational diseases. The authors discuss the evidence supporting the involvement of the IIS pathway in modulating the PN and regulating proteostasis in Caenorhabditis elegans. Furthermore, they review previous PN and IIS drug screens and explore the possibility of using C. elegans for whole organism-based drug discovery for modulators of IIS-proteostasis pathways.
  
  
  CONCLUSIONS
  An alternative approach to develop individualized therapy for each conformational disease is to modulate the global PN. The involvement of the IIS pathway in regulating longevity and response to a variety of stresses is well documented. Increasing data now provide evidence for the close association between the IIS and the PN pathways. The authors believe that high-throughput screening campaigns, which target the C. elegans IIS pathway, may identify drugs that are efficacious in treating numerous conformational diseases.
authors.affiliation: University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of UPMC and Magee-Womens Hospital Research Institute, Department of Pediatrics , 4401 Penn Avenue, Rangos Room 7131, Pittsburgh, PA 15224 , USA +1 412 692 9457 ; +1 412 641 1844 ; paksc@upmc.edu.
authors.forename: Linda P
authors.initials: LP
authors.lastname: O'Reilly
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Benson
authors.forename: Erin E
authors.initials: EE
authors.lastname: Cummings
authors.forename: David H
authors.initials: DH
authors.lastname: Perlmutter
authors.forename: Gary A
authors.initials: GA
authors.lastname: Silverman
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pak
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D055808:Drug Discovery / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D007328:Insulin / Q000502:physiology; D008136:Longevity / Q000502:physiology; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D013002:Somatomedins / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D007328:Insulin; D013002:Somatomedins
keywords: Caenorhabditis elegans; conformational disease; drug discovery; insulin signaling; proteostasis network