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Co-expression of a disease-associated lysozyme variant with human lysozyme in Drosophila causes accumulation of amyloid deposits and neurodegeneration
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Lysozyme amyloidosis is a dominantly inherited form of amyloid disease. Mutant variants of the protein, with increased tendencies to aggregate compared to the wild type (WT), accumulate in large amyloid deposits in multiple organs, eventually leading to organ failure. Humans affected by lysozyme amyloidosis carry one allele for the wild type protein and one allele encoding for a mutant variant of lysozyme. We have used a Drosophila melanogaster model to investigate the effect of co-expressing WT lysozyme and a mutated variant, F57I, in the central nervous system (CNS) of the fly. In this study, using activity and longevity assays, WT-F57I flies showed a lower activity and a shorter lifespan than flies expressing only WT or the F57I variant of lysozyme (median survival 16 days compared to 34 and 23 respectively). This indicates deteriorating neurological functions in WT-F57I flies; exceeding the decrease in neurological function previously observed for flies only expressing the mutated variant, F57I. In addition, accumulation of insoluble species with amyloid structure was detected for the WT-F57I flies but not for the WT or the F57I flies. Our study show that co-expression of WT lysozyme and the amyloidogenic variant F57I results in neurological damage and is required for accumulation of amyloid deposits, which is characteristic for the disease observed in humans. Our data suggest that insoluble amyloid species or intermediate species, formed on the pathway toward amyloid species, may be cytotoxic and thus contribute to the impaired neurological functions observed for the WT-F57I flies.

National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-106645OAI: oai:DiVA.org:liu-106645DiVA: diva2:717657
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2014-05-16Bibliographically approved
In thesis
1. Understanding the dual nature of lysozyme: part villain – part hero: A Drosophila melanogaster model of lysozyme amyloidosis
Open this publication in new window or tab >>Understanding the dual nature of lysozyme: part villain – part hero: A Drosophila melanogaster model of lysozyme amyloidosis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Amyloid proteins are a distinct class of proteins that can misfold into β-sheet rich structures that later mature to form the characteristic species known as amyloid fibrils, and accumulate in tissues in the human body. The misfolding event is often caused by mutations (or outer factors such as changes in pH) that destabilize the native protein structure. The mature amyloid fibrils were initially believed to be associated with diseases connected to protein misfolding such as Alzheimer’s disease (AD), Parkinson’s disease, transthyretin amyloidosis and lysozyme amyloidosis. However, now it is known that many different factors are involved in these diseases such as failure in protein clearance, lysosomal dysfunction and formation of intermediate misfolded protein species, which possess cytotoxic properties, preceding the formation of mature fibrils.

In this thesis the amyloidogenic protein lysozyme has been examined in vivo by using Drosophila melanogaster (fruit fly) as a model organism. The effects of over-expressing human lysozyme and amyloidogenic variants in Drosophila have been investigated both in the absence and presence of the serum amyloid P component (SAP), a protein known to interact with amyloid species. In addition, the role of lysozyme in AD has been investigated by  co-expressing human lysozyme and amyloid β in Drosophila.

The lysozyme protein is an enzyme naturally found in bodily fluids such as tears, breast milk and saliva. It is engaged in the body’s defense and acts by hydrolyzing the cell wall of invading bacteria. Certain disease-associated point mutations in the gene encoding lysozyme destabilize the protein and cause it to misfold which results in systemic amyloidosis. To investigate the in vivo misfolding behavior of lysozyme we developed and established a Drosophila model of lysozyme amyloidosis. SAP is commonly found attached to amyloid deposits in the body; however, the role of SAP in amyloid diseases is unknown. To investigate the effect of SAP in lysozyme misfolding, these two proteins were co-expressed in Drosophila.

The amyloid β peptide is involved in AD, building up the plaques found in AD patient brains. These plaques trigger neuroinflammation and since lysozyme is upregulated during various inflammation conditions, a possible role of lysozyme in AD was investigated by overexpressing lysozyme in a Drosophila model of AD. Interaction between lysozyme and the amyloid β protein was also studied by biophysical measurements.

During my work with this thesis, the dual nature of lysozyme emerged; on the one hand a villain, twisted by mutations, causing the lysozyme amyloidosis disease. On the other hand a hero, delaying the toxicity and maybe the neurological damage caused by the amyloid β peptide.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 67 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1574
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-106647 (URN)10.3384/diss.diva-106647 (DOI)978-91-7519-405-9 (ISBN)
Public defence
2014-05-05, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (English)
Opponent
Supervisors
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2014-05-19Bibliographically approved

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Bergkvist, LizaHelmfors, LindaBrorsson, Ann-Christin

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