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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease
EMBO Journal, Volume 31, No. 1, Year 2012
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Description
The extent of proteolytic processing of the amyloid precursor protein (APP) into neurotoxic amyloid-β (Aβ) peptides is central to the pathology of Alzheimer's disease (AD). Accordingly, modifiers that increase Aβ production rates are risk factors in the sporadic form of AD. In a novel systems biology approach, we combined quantitative biochemical studies with mathematical modelling to establish a kinetic model of amyloidogenic processing, and to evaluate the influence by SORLA/SORL1, an inhibitor of APP processing and important genetic risk factor. Contrary to previous hypotheses, our studies demonstrate that secretases represent allosteric enzymes that require cooperativity by APP oligomerization for efficient processing. Cooperativity enables swift adaptive changes in secretase activity with even small alterations in APP concentration. We also show that SORLA prevents APP oligomerization both in cultured cells and in the brain in vivo, eliminating the preferred form of the substrate and causing secretases to switch to a less efficient non-allosteric mode of action. These data represent the first mathematical description of the contribution of genetic risk factors to AD substantiating the relevance of subtle changes in SORLA levels for amyloidogenic processing as proposed for patients carrying SORL1 risk alleles. © 2012 European Molecular Biology Organization | All Rights Reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3252570/bin/emboj2011352s1.pdf
https://efashare.b-cdn.net/share/pmc/articles/PMC3252570/bin/emboj2011352s2.pdf
Authors & Co-Authors
Schmidt, Vanessa
Germany, Berlin
Max Delbruck Center for Molecular Medicine
Baum, Katharina
Germany, Berlin
Max Delbruck Center for Molecular Medicine
Lao, Angelyn Relucio
Germany, Rostock
Universität Rostock
Rateitschak, Katja
Germany, Rostock
Universität Rostock
Schmitz, Yvonne
Germany, Rostock
Universität Rostock
Teichmann, Anke
Germany, Berlin
Leibniz-institut Für Molekulare Pharmakologie
Wiesner, Burkhard
Germany, Berlin
Leibniz-institut Für Molekulare Pharmakologie
Munck, Claus
Unknown Affiliation
Petersen, Claus Munck
Denmark, Aarhus
Aarhus Universitet
Nykjaer, Anders
Denmark, Aarhus
Aarhus Universitet
Wolf, Jana X.
Germany, Berlin
Max Delbruck Center for Molecular Medicine
Wolkenhauer, Olaf
Germany, Rostock
Universität Rostock
South Africa, Stellenbosch
Stellenbosch Institute for Advanced Study
Willnow, Thomas E.
Germany, Berlin
Max Delbruck Center for Molecular Medicine
Statistics
Citations: 77
Authors: 13
Affiliations: 5
Identifiers
Doi:
10.1038/emboj.2011.352
ISSN:
02614189
e-ISSN:
14602075
Research Areas
Genetics And Genomics
Study Approach
Quantitative