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Amyloid-? and lysozyme proteotoxicity in Drosophila

Relesde on 2017-05-16February 27, 2023 by Liza Bergkvist

Author : Liza Bergkvist
Publisher : Linköping University Electronic Press
ISBN 13 : 9176855066
Total Pages : 91 pages
Book Rating : 4.7/5 (685 download)

Download or read book Amyloid-? and lysozyme proteotoxicity in Drosophila written by Liza Bergkvist and published by Linköping University Electronic Press. This book was released on 2017-05-16 with total page 91 pages. Available in PDF, EPUB and Kindle. Book excerpt: In the work presented this thesis, two different conditions that are classified as protein misfolding diseases: Alzheimer's disease and lysozyme amyloidosis and proteins that could have a beneficial effect in these diseases, have been studied using Drosophila melanogaster, commonly known as the fruit fly. The fruit fly has been used for over 100 years to study and better understand fundamental biological processes. Although the fruit fly, unlike humans, is an invertebrate, many of its central biological mechanisms are very similar to ours. The first transgenic flies were designed in the early 1980s, and since then, the fruit fly has been one of the most widely used model organisms in studies on the effects of over-expressed human proteins in a biological system; one can regard the fly as a living, biological test tube. For most proteins, it is necessary that they fold into a three-dimensional structure to function properly. But sometimes the folding goes wrong; this may be due to mutations that make the protein unstable and subject to misfolding. A misfolded protein molecule can then aggregate with other misfolded proteins. In Alzheimer's disease, which is the most common form of dementia, protein aggregates are present in the brains of patients. These aggregates are composed of the amyloid-? (A?) peptide, a small peptide of around 42 amino acids which is cleaved from the larger, membrane-bound, protein A?PP by two different enzymes, BACE1 and ?-secretase. In the first part of this thesis, two different fly models for Alzheimer’s disease were used: the A? fly model, which directly expresses the A? peptide, and the A?PP-BACE1 fly model, in which all the components necessary to produce the A? peptide in the fly are expressed in the fly central nervous system (CNS). The two different fly models were compared and the results show that a significantly smaller amount of the A? peptide is needed to achieve the same, or an even greater, toxic effect in the A?PP-BACE1 model compared to the A? model. In the second part of the thesis, these two fly models for Alzheimer’s disease were again used, but now to investigate whether lysozyme, a protein involved in our innate immune system, can counteract the toxic effect of A? generated in the fly models. And indeed, lysozyme is able to save the flies from A?-induced toxicity. A? and lysozyme were found to interact with each other in vivo. The second misfolding disease studied in this thesis is lysozyme amyloidosis. It is a rare, dominantly inherited amyloid disease in which mutant variants of lysozyme give rise to aggregates, weighing up to several kilograms, that accumulate around the kidneys and liver, eventually leading to organ failure. In the third part of this thesis, a fly model for lysozyme amyloidosis was used to study the effect of co-expressing the serum amyloid P component (SAP), a protein that is part of all protein aggregates found within this disease class. SAP is able to rescue the toxicity induced by expressing the mutant variant of lysozyme, F57I, in the fly's CNS. To further investigate how SAP was able to do this, double-expressing lysozyme flies, which exhibit stronger disease phenotypes than those of the single-expressing lysozyme flies previously studied, were used in the fourth part of this thesis. SAP was observed to reduce F57I toxicity and promote F57I to form aggregates with more distinct amyloid characteristics. In conclusion, the work included in this thesis demonstrates that: i) A? generated from A?PP processing in the fly CNS results in higher proteotoxicity compared with direct expression of A? from the transgene, ii) lysozyme can prevent A? proteotoxicity in Drosophila and could thus be a potential therapeutic molecule to treat Alzheimer’s disease and iii) in a Drosophila model of lysozyme amyloidosis, SAP can prevent toxicity from the disease-associated lysozyme variant F57I and promote formation of aggregated lysozyme morphotypes with amyloid properties; this is important to take into account when a reduced level of SAP is considered as a treatment strategy for lysozyme amyloidosis.