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HIAPP and hproIAPP triggers elective autophagy and inhibit the neuro-­protective effect of autophagy
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Department of Medical Cell Biology, Uppsala University, SE-­‐75123, Uppsala, Sweden.
Centre for Cancer Biomedicine, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, N-­‐0317, Oslo, Norway.
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Health Sciences.
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2010 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: Amyloid formation is associated with cell death and islet amyloid is thought to participate in the 50-60% β-cell reduction detected in patients with type 2 diabetes. Islet amyloid polypeptide (IAPP) is the main amyloid protein in the islets of Langerhans. Initial IAPP-amyloid formation is intracellular and part of this amyloid constitutes of proIAPP.

Material & methods: We have established a new model in Drosophila melanogaster where expression of hproIAPP and IAPP results in the formation of amyloid. With this model, we have investigated the effect of protein aggregation on pathways such as ER-stress, unfolded protein response (UPR), apoptosis and autophagy. Important steps in the different pathways were manipulated by RNAi-technique or over- expression of endogenous Drosophila proteins.

Results: Expression of hproIAPP and hIAPP driven to the pdf-neurons led to cell death, but this was without activation of ER-stress, UPR or apoptosis. Aggregated hproIAPP and IAPP, labeled with antibodies against ubiquitin and p62 were accumulated intracellular, a finding that points to an involvement of autophagy. HproIAPP and hIAPP were shown to exert their toxic activity by an intracellular mechanism in contrary to Aβ42 and Aβ42 E22G that exhibit an extracellular toxic activity.

Conclusion: Studies on toxicity suggest that hproIAPP and hIAPP aggregates can occupy the autophagy pathway and prevent maintenance of basal cellular homeostasis. Comparison of proIAPP/IAPP and Aβ42 toxicity shows that amyloid proteins of separate origin can exhibit different toxicity.

Place, publisher, year, edition, pages
2010. Vol. 17, 44-45 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-70093OAI: diva2:435438
Available from: 2011-08-18 Created: 2011-08-18 Last updated: 2011-08-18Bibliographically 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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