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Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, Faculty of Science & Engineering.ORCID iD: 0000-0002-5582-140X
Uppsala University.
2011 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 6, no 6Article in journal (Refereed) Published
Abstract [en]

Background: Recent research supports that aggregation of islet amyloid polypeptide (IAPP) leads to cell death and this makes islet amyloid a plausible cause for the reduction of beta cell mass, demonstrated in patients with type 2 diabetes. IAPP is produced by the beta cells as a prohormone, and proIAPP is processed into IAPP by the prohormone convertases PC1/3 and PC2 in the secretory granules. Little is known about the pathogenesis for islet amyloid and which intracellular mechanisms are involved in amyloidogenesis and induction of cell death.

Methodology/Principal Findings: We have established expression of human proIAPP (hproIAPP), human IAPP (hIAPP) and the non-amyloidogenic mouse IAPP (mIAPP) in Drosophila melanogaster, and compared survival of flies with the expression driven to different cell populations. Only flies expressing hproIAPP in neurons driven by the Gal4 driver elavC(155,Gal4) showed a reduction in lifespan whereas neither expression of hIAPP or mIAPP influenced survival. Both hIAPP and hproIAPP expression caused formation of aggregates in CNS and fat body region, and these aggregates were both stained by the dyes Congo red and pFTAA, both known to detect amyloid. Also, the morphology of the highly organized protein granules that developed in the fat body of the head in hIAPP and hproIAPP expressing flies was characterized, and determined to consist of 15.8 nm thick pentagonal rod-like structures.

Conclusions/Significance: These findings point to a potential for Drosophila melanogaster to serve as a model system for studies of hproIAPP and hIAPP expression with subsequent aggregation and developed pathology.

Place, publisher, year, edition, pages
Public Library of Science (PLoS) , 2011. Vol. 6, no 6
National Category
Engineering and Technology
URN: urn:nbn:se:liu:diva-69857DOI: 10.1371/journal.pone.0020221ISI: 000291682300005OAI: diva2:433429

Original Publication: Sebastian Schultz, Peter Nilsson and Gunilla Torstensdotter Westermark, Drosophila Melanogaster as a Model System for Studies of Islet Amyloid Polypeptide Aggregation, 2011, PLoS ONE, (6), 6. Copyright: Public Library of Science (PLoS)

Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2015-05-28Bibliographically approved
In thesis
1. Studies on Islet Amyloid Polypeptide Aggregation: From Model Organism to Molecular Mechanisms
Open this publication in new window or tab >>Studies on Islet Amyloid Polypeptide Aggregation: From Model Organism to Molecular Mechanisms
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The proper folding of a protein into its defined three--‐dimensional structure is one of the many fundamental challenges a cell encounters. A number of tightly controlled pathways have evolved to assist in the proper folding of a protein, but also to aid in the removal of misfolded proteins. Despite the presence of these pathways accumulation of misfolded proteins can still occur. Amyloid deposits consist of misfolded proteins with a characteristic highly ordered fibrillar structure that will exert affinity for the amyloid dye Congo red and has a unique X-ray diffraction pattern. Currently 27 different proteins have been identified as amyloid forming proteins in human, however the exact role of amyloid in the pathogenesis of the connected disease is most often unclear.

Islet amyloid is made up of the beta cell derived hormone islet amyloid polypeptide (IAPP) and is associated with the development of type 2 diabetes. Propagation of IAPP-fibrils is believed to be one important cause of the pancreatic beta cell death detected in patients with type 2 diabetes. IAPP is a naturally occurring polypeptide hormone stored and secreted together with insulin. IAPP and insulin arise from posttranslational processing of their biological inactive precursors proIAPP and proinsulin. In addition to human, cat and monkey IAPP will form amyloid deposits in conditions resembling human type 2 diabetes. However, IAPP from mouse and rat do not form amyloid as a result of the differences in amino acid sequence.

My main research goal was to establish a unique model system suitable to study the effects of proIAPP and IAPP aggregation. I selected Drosophila melanogaster due to its many suitable characteristics as a model organism and its superior genetic toolbox. I have demonstrated that over--‐expression of hproIAPP and hIAPP in the central nervous system (CNS) results in aggregate formation in the brain and neighbouring fat body. Consistent with previous studies, expression of mIAPP does not result in the formation of aggregates. To investigate the intracellular effects of hproIAPP and hIAPP aggregation on a specific population of neurons, we targeted the expression of these peptides specifically to 16 neurons in the brain, the pdf- neurons. These pdf-neurons are divided into 2 clusters of 8 cells per brain hemisphere. First I showed that expression of aggregation prone hIAPP and hproIAPP resulted in significant death of the 8 cells, whereas expression of mIAPP had no such effect. In efforts to pinpoint the mechanisms behind the observed cell death I demonstrated that hproIAPP and hIAPP both pass the ERs quality control for protein folding and that the initiated cell death does not occur through classical apoptosis. Instead, selective autophagy is activated by hIAPP and hproIAPP. This activation counteracts the usually neuro-protective effects of autophagy and contributes to cell death. Strikingly, I also showed that Aâ, the amyloid protein implicated in Alzheimer’s disease, does not exhibit any intracellular toxicity when expressed in pdf-cells. This supports the existence of separate toxic pathways for different amyloid proteins.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 100 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1254
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-70094 (URN)978-­‐91-­‐7393-­‐099-­‐4 (ISBN)
Public defence
2011-09-16, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2011-08-18 Created: 2011-08-18 Last updated: 2011-09-12Bibliographically approved

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