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Luminescent Conjugated Oligothiophenes for Sensitive Fluorescent Assignment of Protein Inclusion Bodies
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry. Linköping University, The Institute of Technology.
Charite, Germany .
University of So Calif, CA USA .
Charite, Germany .
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2013 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 14, no 5, 607-616 p.Article in journal (Refereed) Published
Abstract [en]

Small hydrophobic ligands identifying intracellular protein deposits are of great interest, as protein inclusion bodies are the pathological hallmark of several degenerative diseases. Here we report that fluorescent amyloid ligands, termed luminescent conjugated oligothiophenes (LCOs), rapidly and with high sensitivity detect protein inclusion bodies in skeletal muscle tissue from patients with sporadic inclusion body myositis (s-IBM). LCOs having a conjugated backbone of at least five thiophene units emitted strong fluorescence upon binding, and showed co-localization with proteins reported to accumulate in s-IBM protein inclusion bodies. Compared with conventional amyloid ligands, LCOs identified a larger fraction of immunopositive inclusion bodies. When the conjugated thiophene backbone was extended with terminal carboxyl groups, the LCO revealed striking spectral differences between distinct protein inclusion bodies. We conclude that 1) LCOs are sensitive, rapid and powerful tools for identifying protein inclusion bodies and 2) LCOs identify a wider range of protein inclusion bodies than conventional amyloid ligands.

Place, publisher, year, edition, pages
Wiley-VCH Verlag Berlin , 2013. Vol. 14, no 5, 607-616 p.
Keyword [en]
amyloid beta-peptides, biosensors, fluorescent probes, luminescent conjugated oligothiophene, protein inclusion body
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-91341DOI: 10.1002/cbic.201200731ISI: 000316285600010OAI: diva2:617420

Funding Agencies|Swedish Foundation for Strategic Research||European Research Council (ERC)||EU||

Available from: 2013-04-23 Created: 2013-04-22 Last updated: 2014-04-08Bibliographically approved
In thesis
1. Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates
Open this publication in new window or tab >>Fluorescent thiophene-based ligands for detection and characterization of disease-associated protein aggregates
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the unique optical properties of fluorescent ligands termed luminescent conjugated oligothiophenes (LCOs) have been used to study a variety of protein aggregates associated with human protein misfolding disease. This heterogeneous group of diseases contains well known and fatal members such as Alzheimer´s and Huntington´s disease and the development of sensitive tools for the detection and characterization of protein aggregates is crucial for unravelling the complexity of these pathologies. Conventionally, the molecular dyes Congo red and thioflavin T (ThT) have been the primary choices for detecting and monitoring protein misfolding events. However, the rigid scaffold of both Congo red and ThT only offers an on or off mode and limits their ability to make fine distinctions at the molecular level. In contrast, LCOs have a flexible conjugated backbone and in addition to detect a broader subset of misfolded proteins, LCO can be used to visualize the heterogeneity of protein aggregates.

The work presented in this thesis has given novel insights regarding the close connection between LCO design and optical performance. By altering the backbone length and the arrangement of substituents as well as replacing thiophene units with moieties affecting conjugation length and conformational freedom, the structural requirements of an optimal LCO for a certain application have been revealed. LCOs having a pentameric thiophene backbone with carboxyl end-groups were able to i) cross the blood-brain barrier and selectively stain cerebral amyloid β (Aβ) plaques, ii) detect non-thioflavinophilic Aβ aggregates and non-congophilic prion aggregates, iii) spectrally discriminate Aβ from tau aggregates and iiii) strongly label protein inclusion bodies. However, in some applications this design was outdone by others and in general, the conjugation length and the level of conformational freedom of the backbone were important determinants of the performance of the LCO.

Overall, the findings in this thesis illustrate how small alterations in the LCO molecular scaffold may have large impact on the ligand properties. The results highlight the importance of having a toolbox of diverse ligands in order to increase our knowledge regarding the complex nature of protein aggregates.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 81 p.
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1518
National Category
Natural Sciences
urn:nbn:se:liu:diva-92772 (URN)978-91-7519-623-7 (ISBN)
Public defence
2013-05-31, Planck, Fysikhuset, Campus Valla, Linköpings universitet, Linköping, 10:15 (Swedish)
Available from: 2013-05-21 Created: 2013-05-21 Last updated: 2014-04-08Bibliographically approved

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Klingstedt, TheréseHäggqvist, BoDanielsson, OlofNilsson, K Peter R
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