title: Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment.
abstract: Type 2 diabetes is a growing public health concern and accounts for approximately 90% of all the cases of diabetes. Besides insulin resistance, type 2 diabetes is characterized by a deficit in β-cell mass as a result of misfolded human islet amyloid polypeptide (h-IAPP) which forms toxic aggregates that destroy pancreatic β-cells. Heat shock proteins (HSP) play an important role in combating the unwanted self-association of unfolded proteins. We hypothesized that Hsp72 (HSPA1A) prevents h-IAPP aggregation and toxicity. In this study, we demonstrated that thermal stress significantly up-regulates the intracellular expression of Hsp72, and prevents h-IAPP toxicity against pancreatic β-cells. Moreover, Hsp72 (HSPA1A) overexpression in pancreatic β-cells ameliorates h-IAPP toxicity. To test the hypothesis that Hsp72 (HSPA1A) prevents aggregation and fibril formation, we established a novel C. elegans model that expresses the highly amyloidogenic human pro-IAPP (h-proIAPP) that is implicated in amyloid formation and β-cell toxicity. We demonstrated that h-proIAPP expression in body-wall muscles, pharynx and neurons adversely affects C. elegans development. In addition, we demonstrated that h-proIAPP forms insoluble aggregates and that the co-expression of h-Hsp72 in our h-proIAPP C. elegans model, increases h-proIAPP solubility. Furthermore, treatment of transgenic h-proIAPP C. elegans with ADAPT-232, known to induce the expression and release of Hsp72 (HSPA1A), significantly improved the growth retardation phenotype of transgenic worms. Taken together, this study identifies Hsp72 (HSPA1A) as a potential treatment to prevent β-cell mass decline in type 2 diabetic patients and establishes for the first time a novel in vivo model that can be used to select compounds that attenuate h-proIAPP aggregation and toxicity.
authors.affiliation: Division of Investigative Pathology, Scott & White Hospital and the Texas A&M Health Science Center, College of Medicine, Temple, Texas, United States of America.
authors.forename: Paola C
authors.initials: PC
authors.lastname: Rosas
authors.affiliation: Division of Investigative Pathology, Scott & White Hospital and the Texas A&M Health Science Center, College of Medicine, Temple, Texas, United States of America.
authors.forename: Ganachari M
authors.initials: GM
authors.lastname: Nagaraja
authors.affiliation: Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.|University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Punit
authors.initials: P
authors.lastname: Kaur
authors.affiliation: Department of Research, Swedish Herbal Institute, Åskloster, Sweden.
authors.forename: Alexander
authors.initials: A
authors.lastname: Panossian
authors.affiliation: Department of Research, Swedish Herbal Institute, Åskloster, Sweden.
authors.forename: Georg
authors.initials: G
authors.lastname: Wickman
authors.affiliation: Department of Biology and Howard Hughes Medical Institute, Texas A&M University, College Station, Texas, United States of America.
authors.forename: L Rene
authors.initials: LR
authors.lastname: Garcia
authors.affiliation: Department for Neuroscience Research, Institutes for Research & Medical Consultancies (IRMC) and Deanship for Scientific Research, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Fahd A
authors.initials: FA
authors.lastname: Al-Khamis
authors.affiliation: Department for Neuroscience Research, Institutes for Research & Medical Consultancies (IRMC) and Deanship for Scientific Research, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Alexzander A A
authors.initials: AA
authors.lastname: Asea
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control* / Q000628:therapy*; D004195:Disease Models, Animal; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058228:Islet Amyloid Polypeptide / Q000737:chemistry* / Q000235:genetics / Q000633:toxicity*; D051379:Mice; D008969:Molecular Sequence Data; D010641:Phenotype; D010936:Plant Extracts / Q000494:pharmacology; D066329:Protein Aggregates; D012995:Solubility
chemical_list: C578624:ADAPT 232; D050884:HSP72 Heat-Shock Proteins; D058228:Islet Amyloid Polypeptide; D010936:Plant Extracts; D066329:Protein Aggregates