αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease

Abstract The etiology of Parkinson’s disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown....

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Autores principales:	Victorio Martin Pozo Devoto, Nicolas Dimopoulos, Matías Alloatti, María Belén Pardi, Trinidad M. Saez, María Gabriela Otero, Lucas Eneas Cromberg, Antonia Marín-Burgin, Maria Elida Scassa, Gorazd B. Stokin, Alejandro F. Schinder, Gustavo Sevlever, Tomás Luis Falzone
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ed7ab461035b478bbf2b97dcb519d281
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spelling	oai:doaj.org-article:ed7ab461035b478bbf2b97dcb519d2812021-12-02T16:06:16ZαSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease10.1038/s41598-017-05334-92045-2322https://doaj.org/article/ed7ab461035b478bbf2b97dcb519d2812017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05334-9https://doaj.org/toc/2045-2322Abstract The etiology of Parkinson’s disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T αSyn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that αSyn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T αSyn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of αSyn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that αSyn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of αSyn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.Victorio Martin Pozo DevotoNicolas DimopoulosMatías AlloattiMaría Belén PardiTrinidad M. SaezMaría Gabriela OteroLucas Eneas CrombergAntonia Marín-BurginMaria Elida ScassaGorazd B. StokinAlejandro F. SchinderGustavo SevleverTomás Luis FalzoneNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Victorio Martin Pozo Devoto Nicolas Dimopoulos Matías Alloatti María Belén Pardi Trinidad M. Saez María Gabriela Otero Lucas Eneas Cromberg Antonia Marín-Burgin Maria Elida Scassa Gorazd B. Stokin Alejandro F. Schinder Gustavo Sevlever Tomás Luis Falzone αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease
description	Abstract The etiology of Parkinson’s disease (PD) converges on a common pathogenic pathway of mitochondrial defects in which α-Synuclein (αSyn) is thought to play a role. However, the mechanisms by which αSyn and its disease-associated allelic variants cause mitochondrial dysfunction remain unknown. Here, we analyzed mitochondrial axonal transport and morphology in human-derived neurons overexpressing wild-type (WT) αSyn or the mutated variants A30P or A53T, which are known to have differential lipid affinities. A53T αSyn was enriched in mitochondrial fractions, inducing significant mitochondrial transport defects and fragmentation, while milder defects were elicited by WT and A30P. We found that αSyn-mediated mitochondrial fragmentation was linked to expression levels in WT and A53T variants. Targeted delivery of WT and A53T αSyn to the outer mitochondrial membrane further increased fragmentation, whereas A30P did not. Genomic editing to disrupt the N-terminal domain of αSyn, which is important for membrane association, resulted in mitochondrial elongation without changes in fusion-fission protein levels, suggesting that αSyn plays a direct physiological role in mitochondrial size maintenance. Thus, we demonstrate that the association of αSyn with the mitochondria, which is modulated by protein mutation and dosage, influences mitochondrial transport and morphology, highlighting its relevance in a common pathway impaired in PD.
format	article
author	Victorio Martin Pozo Devoto Nicolas Dimopoulos Matías Alloatti María Belén Pardi Trinidad M. Saez María Gabriela Otero Lucas Eneas Cromberg Antonia Marín-Burgin Maria Elida Scassa Gorazd B. Stokin Alejandro F. Schinder Gustavo Sevlever Tomás Luis Falzone
author_facet	Victorio Martin Pozo Devoto Nicolas Dimopoulos Matías Alloatti María Belén Pardi Trinidad M. Saez María Gabriela Otero Lucas Eneas Cromberg Antonia Marín-Burgin Maria Elida Scassa Gorazd B. Stokin Alejandro F. Schinder Gustavo Sevlever Tomás Luis Falzone
author_sort	Victorio Martin Pozo Devoto
title	αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease
title_short	αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease
title_full	αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease
title_fullStr	αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease
title_full_unstemmed	αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease
title_sort	αsynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with parkinson’s disease
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ed7ab461035b478bbf2b97dcb519d281
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αSynuclein control of mitochondrial homeostasis in human-derived neurons is disrupted by mutations associated with Parkinson’s disease

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