Fly model of type 2 diabetes: processing of proIAPP makes a difference
2010 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, Vol. 17, no S1, 44-45 p.Article in journal, Meeting abstract (Other academic) Published
Patients with type 2 diabetes have a marked reducedbeta cell mass and fail to produce sufficient amounts of insulin required for regulation of glucose home- ostasis. Recent research supports that intracellular aggregation of islet amyloid polypeptide (IAPP) leads to cell death and therefore makes IAPP aggregation a plausible cause for the beta cell reduction. Little is known about the mechanisms that precede amyloid formation or which cellular pathways are involved in this process. To gain better understanding we haveestablished a Drosophila melanogaster model, where GAL4 drives expression of UAS-targeted transgenes in a cell or tissue specific pattern. The fruit fly offers a unique option to manipulate any cellular pathway with different genetic tools. The knowledge that*70% of all Drosophila melanogaster genes have anorthologue in humans stress the potential for path- ways found in D. melanogaster to be of importance in humans as well. Transgenic flies expressing human proIAPP (the precursor of IAPP) and IAPP and the non-amyloidogenic mouse IAPP (mIAPP) have been generated. Expression of proIAPP in the brain reduced the lifespan of the fly whereas neither IAPP nor mIAPP expression influenced survival. Immu- nolabelling with an antibody raised against human IAPP and that cross-reacts with murine IAPP labelled neurons in all three strains, whereas a concomitant loss of cell nuclei only appeared during proIAPP and IAPP expression. Furthermore, we detected an early potentiated activation of the autophagy pathway in proIAPP flies. Interestingly, even though IAPP expression was not related to a shorter lifespan, both IAPP and proIAPP expression in the central nervous system led to amyloid deposition in the fat body of the head as shown with Congo red and pFTAA, a newly synthesised luminescent conjugated polymer. Our results de- monstrate that D. melanogaster has a great potential as a model for studies of proIAPP and IAPP expression with subsequent amyloid formation and connected cellular response mechanisms. The find- ing that proIAPP aggregation seems to exert a more toxic impact at a cellular level is in line with ourresults from mammalian cell lines.
Place, publisher, year, edition, pages
Informa Healthcare, 2010. Vol. 17, no S1, 44-45 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-60255DOI: 10.3109/13506121003737401ISI: 000279801500016OAI: oai:DiVA.org:liu-60255DiVA: diva2:355798
XII INTERNATIONAL SYMPOSIUM ON AMYLOIDOSIS, 'From Molecular Mechanisms Toward the Cure of Systemic Amyloidoses', Rome, Italy, April 18–21, 2010