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Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity

Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer’s disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulat...

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Autores principales: Shields, Lauren Y., Li, Huihui, Nguyen, Kevin, Kim, Hwajin, Doric, Zak, Garcia, Joseph H., Gill, T. Michael, Haddad, Dominik, Vossel, Keith, Calvert, Meredith, Nakamura, Ken
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042169/
https://www.ncbi.nlm.nih.gov/pubmed/33639169
http://dx.doi.org/10.1016/j.jbc.2021.100469
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author Shields, Lauren Y.
Li, Huihui
Nguyen, Kevin
Kim, Hwajin
Doric, Zak
Garcia, Joseph H.
Gill, T. Michael
Haddad, Dominik
Vossel, Keith
Calvert, Meredith
Nakamura, Ken
author_facet Shields, Lauren Y.
Li, Huihui
Nguyen, Kevin
Kim, Hwajin
Doric, Zak
Garcia, Joseph H.
Gill, T. Michael
Haddad, Dominik
Vossel, Keith
Calvert, Meredith
Nakamura, Ken
author_sort Shields, Lauren Y.
collection PubMed
description Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer’s disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca(2+) (mitoCa(2+)) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca(2+). This mitoCa(2+) overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.
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spelling pubmed-80421692021-04-15 Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity Shields, Lauren Y. Li, Huihui Nguyen, Kevin Kim, Hwajin Doric, Zak Garcia, Joseph H. Gill, T. Michael Haddad, Dominik Vossel, Keith Calvert, Meredith Nakamura, Ken J Biol Chem Research Article Alterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer’s disease (AD). However, we understand very little about the normal functions of fission or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related protein 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca(2+) (mitoCa(2+)) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca(2+). This mitoCa(2+) overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology. American Society for Biochemistry and Molecular Biology 2021-02-25 /pmc/articles/PMC8042169/ /pubmed/33639169 http://dx.doi.org/10.1016/j.jbc.2021.100469 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Shields, Lauren Y.
Li, Huihui
Nguyen, Kevin
Kim, Hwajin
Doric, Zak
Garcia, Joseph H.
Gill, T. Michael
Haddad, Dominik
Vossel, Keith
Calvert, Meredith
Nakamura, Ken
Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
title Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
title_full Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
title_fullStr Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
title_full_unstemmed Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
title_short Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
title_sort mitochondrial fission is a critical modulator of mutant app-induced neural toxicity
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042169/
https://www.ncbi.nlm.nih.gov/pubmed/33639169
http://dx.doi.org/10.1016/j.jbc.2021.100469
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