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Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain

Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in en...

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Autores principales: Rossini, Michela, García-Casas, Paloma, Filadi, Riccardo, Pizzo, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394530/
https://www.ncbi.nlm.nih.gov/pubmed/34440738
http://dx.doi.org/10.3390/cells10081968
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author Rossini, Michela
García-Casas, Paloma
Filadi, Riccardo
Pizzo, Paola
author_facet Rossini, Michela
García-Casas, Paloma
Filadi, Riccardo
Pizzo, Paola
author_sort Rossini, Michela
collection PubMed
description Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca(2+) handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER–mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca(2+) crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER–mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER–mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling.
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spelling pubmed-83945302021-08-28 Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain Rossini, Michela García-Casas, Paloma Filadi, Riccardo Pizzo, Paola Cells Article Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca(2+) handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER–mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca(2+) crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER–mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER–mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling. MDPI 2021-08-03 /pmc/articles/PMC8394530/ /pubmed/34440738 http://dx.doi.org/10.3390/cells10081968 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rossini, Michela
García-Casas, Paloma
Filadi, Riccardo
Pizzo, Paola
Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain
title Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain
title_full Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain
title_fullStr Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain
title_full_unstemmed Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain
title_short Loosening ER–Mitochondria Coupling by the Expression of the Presenilin 2 Loop Domain
title_sort loosening er–mitochondria coupling by the expression of the presenilin 2 loop domain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394530/
https://www.ncbi.nlm.nih.gov/pubmed/34440738
http://dx.doi.org/10.3390/cells10081968
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