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Published on: September 30, 2011
Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes
Paola C Rosas1, Ganachari M Nagaraja1, Punit Kaur2,3
1Division of Investigative Pathology, Scott & White Hospital and the Texas A&M Health Science Center, College of Medicine, Temple, Texas, United States of America.
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.
Insights
Heat shock protein 72 (Hsp72) prevents toxic aggregation of human islet amyloid polypeptide (h-IAPP), a key factor in type 2 diabetes. This study establishes Hsp72 as a potential therapeutic target to protect pancreatic beta-cells.
Area of Science:
- Molecular Biology
- Endocrinology
- Neuroscience
Background:
- Type 2 diabetes is a major public health issue, with 90% of cases linked to insulin resistance and beta-cell loss.
- Misfolded human islet amyloid polypeptide (h-IAPP) forms toxic aggregates, leading to pancreatic beta-cell destruction and reduced beta-cell mass.
- Heat shock proteins (HSPs) are known to prevent protein misfolding and aggregation.
Purpose of the Study:
- To investigate the role of Hsp72 (HSPA1A) in preventing h-IAPP aggregation and toxicity.
- To establish a novel in vivo model for studying h-IAPP aggregation and identifying potential therapeutic compounds.
Main Methods:
- Examined the effect of thermal stress on Hsp72 expression and h-IAPP toxicity in pancreatic beta-cells.
- Overexpressed Hsp72 (HSPA1A) in pancreatic beta-cells to assess its protective effects.
- Developed a novel C. elegans model expressing amyloidogenic human pro-IAPP (h-proIAPP) to study aggregation and toxicity in vivo.
- Co-expressed h-Hsp72 with h-proIAPP in C. elegans to evaluate its impact on solubility.
- Treated transgenic C. elegans with ADAPT-232, a known Hsp72 inducer, to assess its effect on h-proIAPP-induced phenotypes.
Main Results:
- Thermal stress significantly increased intracellular Hsp72 expression and protected beta-cells from h-IAPP toxicity.
- Hsp72 (HSPA1A) overexpression ameliorated h-IAPP-induced toxicity in pancreatic beta-cells.
- h-proIAPP expression in C. elegans caused developmental defects and formed insoluble aggregates.
- Co-expression of h-Hsp72 increased h-proIAPP solubility in the C. elegans model.
- ADAPT-232 treatment significantly improved growth retardation in h-proIAPP transgenic worms by inducing Hsp72.
Conclusions:
- Hsp72 (HSPA1A) plays a crucial role in preventing h-IAPP aggregation and subsequent beta-cell toxicity.
- Hsp72 (HSPA1A) represents a promising therapeutic target for preventing beta-cell mass decline in type 2 diabetes.
- The developed C. elegans model provides a valuable tool for screening compounds that mitigate h-IAPP aggregation and toxicity.
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