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SAP to the rescue: Serum amyloid p component ameliorates neurological damage caused by expressing a lysozyme variant in the central nervous system of Drosophila melanogaster
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 hereditary disease in which mutations in the gene encoding lysozyme leads to misfolding and consequently accumulation of amyloid material. To improve understanding of the processes involved we expressed human wild type (WT) lysozyme and the disease-associated variant F57I in the central nervous system (CNS) of a Drosophila melanogaster model of lysozyme amyloidosis, with and without serum amyloid p component (SAP). We found that flies expressing the amyloidogenic variant F57I in the CNS have a shorter lifespan and lower locomotor activity than flies expressing WT lysozyme or control flies, indicating that the flies’ neurological functions are impaired when F57I is expressed in the nerve cells. In addition, the Unfolded Protein Response (UPR) was upregulated in the F57I-expressing flies. However, co-expression of SAP in the CNS restored the F57I flies’ locomotor activity and lifespan. Thus, SAP has apparent ability to protect nerve cells from damage caused by F57I. Furthermore, co-expression of SAP prevented accumulation of insoluble forms of lysozyme in both WT- and F57I-expressing flies and delayed up-regulation of the UPR by 10 days in F57I flies. Our findings suggest that SAP can prevent cytotoxic effects of expressing F57I in fly CNS by retaining F57I in a soluble form and preventing crowding of misfolded F57I species in the endoplasmic reticulum.

Keyword [en]
xbp1-EGFP, ER stress, iFly, Amyloidosis, Misfolding
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:liu:diva-106644OAI: oai:DiVA.org:liu-106644DiVA: diva2:717654
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2014-05-16
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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Helmfors, LindaBergkvist, LizaBrorsson, Ann-Christin

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