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Sequestration of th...
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Luheshi, Leila M.University of Cambridge
(author)
Sequestration of the A beta Peptide Prevents Toxicity and Promotes Degradation In Vivo
- Article/chapterEnglish2010
Publisher, publication year, extent ...
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2010-03-16
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Public Library of Science (PLoS),2010
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printrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:kth-27565
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https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-27565URI
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https://doi.org/10.1371/journal.pbio.1000334DOI
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https://res.slu.se/id/publ/48165URI
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https://gup.ub.gu.se/publication/121071URI
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https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-60812URI
Supplementary language notes
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Language:English
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Summary in:English
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Classification
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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QC 20101215
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Protein aggregation, arising from the failure of the cell to regulate the synthesis or degradation of aggregation-prone proteins, underlies many neurodegenerative disorders. However, the balance between the synthesis, clearance, and assembly of misfolded proteins into neurotoxic aggregates remains poorly understood. Here we study the effects of modulating this balance for the amyloid-beta (A beta) peptide by using a small engineered binding protein (Z(A beta 3)) that binds with nanomolar affinity to A beta, completely sequestering the aggregation-prone regions of the peptide and preventing its aggregation. Co-expression of Z(A beta 3) in the brains of Drosophila melanogaster expressing either A beta(42) or the aggressive familial Alzheimer's disease (AD) associated E22G variant of A beta(42) abolishes their neurotoxic effects. Biochemical analysis indicates that monomer A beta binding results in degradation of the peptide in vivo. Complementary biophysical studies emphasize the dynamic nature of A beta aggregation and reveal that Z(A beta 3) not only inhibits the initial association of A beta monomers into oligomers or fibrils, but also dissociates pre-formed oligomeric aggregates and, although very slowly, amyloid fibrils. Toxic effects of peptide aggregation in vivo can therefore be eliminated by sequestration of hydrophobic regions in monomeric peptides, even when these are extremely aggregation prone. Our studies also underline how a combination of in vivo and in vitro experiments provide mechanistic insight with regard to the relationship between protein aggregation and clearance and show that engineered binding proteins may provide powerful tools with which to address the physiological and pathological consequences of protein aggregation.
Subject headings and genre
Added entries (persons, corporate bodies, meetings, titles ...)
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Hoyer, WolfgangGothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology,University of Gothenburg(Swepub:gu)xhoywo
(author)
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de Barros, Teresa PereiraUniversity of Cambridge
(author)
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Härd, Iris van Dijk,1966Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology,University of Gothenburg(Swepub:gu)xharir
(author)
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Brorsson, Ann-ChristinUniversity of Cambridge(Swepub:liu)annbr05
(author)
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Macao, Bertil,1969Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi,Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology,University of Gothenburg(Swepub:gu)xmacbe
(author)
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Persson, Cecilia,1974Gothenburg University,Göteborgs universitet,Svenskt NMR-centrum vid Göteborgs universitet,Swedish NMR Centre at Göteborg University,University of Gothenburg(Swepub:gu)xengmc
(author)
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Crowther, Damian C.University of Cambridge
(author)
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Lomas, David A.University of Cambridge
(author)
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Ståhl, StefanKTH,Molekylär Bioteknologi,Royal Institute of Technology (KTH), Stockholm(Swepub:kth)u1svy8i4
(author)
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Dobson, Christopher M.University of Cambridge
(author)
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Härd, TorleifGothenburg University,Göteborgs universitet,Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för molekylärbiologi,Department of Molecular Biology,Svenskt NMR-centrum vid Göteborgs universitet,Swedish NMR Centre at Göteborg University,University of Gothenburg(Swepub:gu)xharto
(author)
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University of CambridgeInstitutionen för biomedicin, avdelningen för medicinsk kemi och cellbiologi
(creator_code:org_t)
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Sveriges lantbruksuniversitet
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In:PLoS biology: Public Library of Science (PLoS)8:3, s. e1000334-1544-91731545-7885
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NATURAL SCIENCES
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MEDICAL AND HEAL ...
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PLoS biology
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Royal Institute of Technology
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Swedish University of Agricultural Sciences
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University of Gothenburg
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Linköping University