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Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations

The enzyme complex γ-secretase generates amyloid β-peptide (Aβ), a 37–43-residue peptide associated with Alzheimer disease (AD). Mutations in presenilin 1 (PS1), the catalytical subunit of γ-secretase, result in familial AD (FAD). A unifying theme among FAD mutations is an alteration in the ratio Aβ...

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Autores principales: Wanngren, Johanna, Lara, Patricia, Öjemalm, Karin, Maioli, Silvia, Moradi, Nasim, Chen, Lu, Tjernberg, Lars O., Lundkvist, Johan, Nilsson, IngMarie, Karlström, Helena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050182/
https://www.ncbi.nlm.nih.gov/pubmed/24918054
http://dx.doi.org/10.1016/j.fob.2014.04.006
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author Wanngren, Johanna
Lara, Patricia
Öjemalm, Karin
Maioli, Silvia
Moradi, Nasim
Chen, Lu
Tjernberg, Lars O.
Lundkvist, Johan
Nilsson, IngMarie
Karlström, Helena
author_facet Wanngren, Johanna
Lara, Patricia
Öjemalm, Karin
Maioli, Silvia
Moradi, Nasim
Chen, Lu
Tjernberg, Lars O.
Lundkvist, Johan
Nilsson, IngMarie
Karlström, Helena
author_sort Wanngren, Johanna
collection PubMed
description The enzyme complex γ-secretase generates amyloid β-peptide (Aβ), a 37–43-residue peptide associated with Alzheimer disease (AD). Mutations in presenilin 1 (PS1), the catalytical subunit of γ-secretase, result in familial AD (FAD). A unifying theme among FAD mutations is an alteration in the ratio Aβ species produced (the Aβ42/Aβ40 ratio), but the molecular mechanisms responsible remain elusive. In this report we have studied the impact of several different PS1 FAD mutations on the integration of selected PS1 transmembrane domains and on PS1 active site conformation, and whether any effects translate to a particular amyloid precursor protein (APP) processing phenotype. Most mutations studied caused an increase in the Aβ42/Aβ40 ratio, but via different mechanisms. The mutations that caused a particular large increase in the Aβ42/Aβ40 ratio did also display an impaired APP intracellular domain (AICD) formation and a lower total Aβ production. Interestingly, seven mutations close to the catalytic site caused a severely impaired integration of proximal transmembrane/hydrophobic sequences into the membrane. This structural defect did not correlate to a particular APP processing phenotype. Six selected FAD mutations, all of which exhibited different APP processing profiles and impact on PS1 transmembrane domain integration, were found to display an altered active site conformation. Combined, our data suggest that FAD mutations affect the PS1 structure and active site differently, resulting in several complex APP processing phenotypes, where the most aggressive mutations in terms of increased Aβ42/Aβ40 ratio are associated with a decrease in total γ-secretase activity.
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spelling pubmed-40501822014-06-10 Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations Wanngren, Johanna Lara, Patricia Öjemalm, Karin Maioli, Silvia Moradi, Nasim Chen, Lu Tjernberg, Lars O. Lundkvist, Johan Nilsson, IngMarie Karlström, Helena FEBS Open Bio Article The enzyme complex γ-secretase generates amyloid β-peptide (Aβ), a 37–43-residue peptide associated with Alzheimer disease (AD). Mutations in presenilin 1 (PS1), the catalytical subunit of γ-secretase, result in familial AD (FAD). A unifying theme among FAD mutations is an alteration in the ratio Aβ species produced (the Aβ42/Aβ40 ratio), but the molecular mechanisms responsible remain elusive. In this report we have studied the impact of several different PS1 FAD mutations on the integration of selected PS1 transmembrane domains and on PS1 active site conformation, and whether any effects translate to a particular amyloid precursor protein (APP) processing phenotype. Most mutations studied caused an increase in the Aβ42/Aβ40 ratio, but via different mechanisms. The mutations that caused a particular large increase in the Aβ42/Aβ40 ratio did also display an impaired APP intracellular domain (AICD) formation and a lower total Aβ production. Interestingly, seven mutations close to the catalytic site caused a severely impaired integration of proximal transmembrane/hydrophobic sequences into the membrane. This structural defect did not correlate to a particular APP processing phenotype. Six selected FAD mutations, all of which exhibited different APP processing profiles and impact on PS1 transmembrane domain integration, were found to display an altered active site conformation. Combined, our data suggest that FAD mutations affect the PS1 structure and active site differently, resulting in several complex APP processing phenotypes, where the most aggressive mutations in terms of increased Aβ42/Aβ40 ratio are associated with a decrease in total γ-secretase activity. Elsevier 2014-04-24 /pmc/articles/PMC4050182/ /pubmed/24918054 http://dx.doi.org/10.1016/j.fob.2014.04.006 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
spellingShingle Article
Wanngren, Johanna
Lara, Patricia
Öjemalm, Karin
Maioli, Silvia
Moradi, Nasim
Chen, Lu
Tjernberg, Lars O.
Lundkvist, Johan
Nilsson, IngMarie
Karlström, Helena
Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations
title Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations
title_full Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations
title_fullStr Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations
title_full_unstemmed Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations
title_short Changed membrane integration and catalytic site conformation are two mechanisms behind the increased Aβ42/Aβ40 ratio by presenilin 1 familial Alzheimer-linked mutations
title_sort changed membrane integration and catalytic site conformation are two mechanisms behind the increased aβ42/aβ40 ratio by presenilin 1 familial alzheimer-linked mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050182/
https://www.ncbi.nlm.nih.gov/pubmed/24918054
http://dx.doi.org/10.1016/j.fob.2014.04.006
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