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Abstract
Expression of the Alzheimer’s disease associated polypeptide Aβ42 and the human polypeptide hormon islet amyloid polypeptide (hIAPP) and the prohormone precursor (hproIAPP) in neurons of Drosophila melanogaster leads to the formation of protein aggregates in the fat body tissue surrounding the brain. We determined the structure of these membrane-encircled protein aggregates using transmission electron microscopy (TEM) and observed the dissolution of protein aggregates after starvation. Electron tomography (ET) as an extension of transmission electron microscopy revealed that these aggregates were comprised of granular subunits having a diameter of 20 nm aligned into highly ordered structures in all three dimensions. The three dimensional (3D) lattice of hIAPP granules were constructed of two unit cells, a body centered tetragonal (BCT) and a triclinic unit cell. A 5-fold twinned structure was observed consisting of the cyclic twinning of the BCT and triclinic unit cells. The interaction between the two nearest hIAPP granules in both unit cells is not only governed by the van der Waals forces and the dipole-dipole interaction but potentially also by filament-like structures that can connect the nearest neighbors. Hence, our 3D structural analysis provides novel insight into the aggregation process of hIAPP in the fat body tissue of Drosophila melanogaster.
Highlights
To enable studies on protein aggregation and amyloid disease development [1], several research groups are using the GAL4-Upstream Activation Sequence (UAS) system to drive cell or tissue specific expression of amyloid proteins in Drosophila melanogaster [2,3,4]
To examine whether formation of this type of aggregates is limited to hproIAPP/human islet amyloid polypeptide (hIAPP) expression, flies expressing Aβ42 were included for the analysis
Five independent flylines with mouse IAPP (mIAPP) expression driven by elavC155-Gal4 were analyzed for the presence of aggregates, but no such aggregates were detected in any fly from these lines (Fig 1G)
Summary
To enable studies on protein aggregation and amyloid disease development [1], several research groups are using the GAL4-UAS system to drive cell or tissue specific expression of amyloid proteins in Drosophila melanogaster [2,3,4]. In the GAL4-UAS system the transcription activator protein Gal binds to the Upstream Activation Sequence (UAS) and activates gene transcription [5]. By selecting a particular Gal line, the protein expression can be directed to a particular population of cells or tissues. We produced a Drosophila melanogaster line expressing human islet amyloid polypeptide (hIAPP).
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