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Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout

Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme γ-secretase, cause familial Alzheimer’s disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predo...

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Autores principales: Arber, Charles, Villegas-Llerena, Claudio, Toombs, Jamie, Pocock, Jennifer M, Ryan, Natalie S, Fox, Nick C, Zetterberg, Henrik, Hardy, John, Wray, Selina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212081/
https://www.ncbi.nlm.nih.gov/pubmed/32395715
http://dx.doi.org/10.1093/braincomms/fcz024
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author Arber, Charles
Villegas-Llerena, Claudio
Toombs, Jamie
Pocock, Jennifer M
Ryan, Natalie S
Fox, Nick C
Zetterberg, Henrik
Hardy, John
Wray, Selina
author_facet Arber, Charles
Villegas-Llerena, Claudio
Toombs, Jamie
Pocock, Jennifer M
Ryan, Natalie S
Fox, Nick C
Zetterberg, Henrik
Hardy, John
Wray, Selina
author_sort Arber, Charles
collection PubMed
description Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme γ-secretase, cause familial Alzheimer’s disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predominantly through gain or loss of function. To address this question, we generated an isogenic allelic series for the PSEN1 mutation intron 4 deletion; represented by control, heterozygous and homozygous mutant induced pluripotent stem cells in addition to a presenilin-1 knockout line. Induced pluripotent stem cell-derived cortical neurons reveal reduced, yet detectable amyloid-beta levels in the presenilin-1 knockout line, and a mutant gene dosage-dependent defect in amyloid precursor protein processing in PSEN1 intron 4 deletion lines, consistent with reduced processivity of γ-secretase. The different effects of presenilin-1 knockout and the PSEN1 intron 4 deletion mutation on amyloid precursor protein-C99 fragment accumulation, nicastrin maturation and amyloid-beta peptide generation support distinct consequences of familial Alzheimer’s disease-associated mutations and knockout of presenilin-1 on the function of γ-secretase.
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spelling pubmed-72120812020-05-11 Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout Arber, Charles Villegas-Llerena, Claudio Toombs, Jamie Pocock, Jennifer M Ryan, Natalie S Fox, Nick C Zetterberg, Henrik Hardy, John Wray, Selina Brain Commun Original Article Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme γ-secretase, cause familial Alzheimer’s disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predominantly through gain or loss of function. To address this question, we generated an isogenic allelic series for the PSEN1 mutation intron 4 deletion; represented by control, heterozygous and homozygous mutant induced pluripotent stem cells in addition to a presenilin-1 knockout line. Induced pluripotent stem cell-derived cortical neurons reveal reduced, yet detectable amyloid-beta levels in the presenilin-1 knockout line, and a mutant gene dosage-dependent defect in amyloid precursor protein processing in PSEN1 intron 4 deletion lines, consistent with reduced processivity of γ-secretase. The different effects of presenilin-1 knockout and the PSEN1 intron 4 deletion mutation on amyloid precursor protein-C99 fragment accumulation, nicastrin maturation and amyloid-beta peptide generation support distinct consequences of familial Alzheimer’s disease-associated mutations and knockout of presenilin-1 on the function of γ-secretase. Oxford University Press 2019-10-14 /pmc/articles/PMC7212081/ /pubmed/32395715 http://dx.doi.org/10.1093/braincomms/fcz024 Text en © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Arber, Charles
Villegas-Llerena, Claudio
Toombs, Jamie
Pocock, Jennifer M
Ryan, Natalie S
Fox, Nick C
Zetterberg, Henrik
Hardy, John
Wray, Selina
Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
title Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
title_full Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
title_fullStr Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
title_full_unstemmed Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
title_short Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
title_sort amyloid precursor protein processing in human neurons with an allelic series of the psen1 intron 4 deletion mutation and total presenilin-1 knockout
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212081/
https://www.ncbi.nlm.nih.gov/pubmed/32395715
http://dx.doi.org/10.1093/braincomms/fcz024
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