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PLoS One. 2016 Mar 9;11(3):e0149409. doi: 10.1371/journal.pone.0149409. eCollection 2016.

Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment.

Author information

1
Division of Investigative Pathology, Scott & White Hospital and the Texas A&M Health Science Center, College of Medicine, Temple, Texas, United States of America.
2
Department of Microbiology, Biochemistry & Immunology, Morehouse School of Medicine, Atlanta, Georgia, United States of America.
3
University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
4
Department of Research, Swedish Herbal Institute, Åskloster, Sweden.
5
Department of Biology and Howard Hughes Medical Institute, Texas A&M University, College Station, Texas, United States of America.
6
Department for Neuroscience Research, Institutes for Research & Medical Consultancies (IRMC) and Deanship for Scientific Research, University of Dammam, Dammam, Saudi Arabia.

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.

PMID:
26960140
PMCID:
PMC4784952
DOI:
10.1371/journal.pone.0149409
[Indexed for MEDLINE]
Free PMC Article

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