Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates

Abstract In neurodegenerative diseases, seeding is a process initiated by the internalization of exogenous protein aggregates. Multiple pathways for internalization of aggregates have been proposed, including direct membrane penetration and endocytosis. To decipher the seeding mechanisms of alpha-sy...

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Autores principales:	Peizhou Jiang, Ming Gan, Shu-Hui Yen, Pamela J. McLean, Dennis W. Dickson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e031185aacef45e083b20d84c1d39615
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spelling	oai:doaj.org-article:e031185aacef45e083b20d84c1d396152021-12-02T12:32:30ZImpaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates10.1038/s41598-017-08149-w2045-2322https://doaj.org/article/e031185aacef45e083b20d84c1d396152017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08149-whttps://doaj.org/toc/2045-2322Abstract In neurodegenerative diseases, seeding is a process initiated by the internalization of exogenous protein aggregates. Multiple pathways for internalization of aggregates have been proposed, including direct membrane penetration and endocytosis. To decipher the seeding mechanisms of alpha-synuclein (αS) aggregates in human cells, we visualized αS aggregation, endo-lysosome distribution, and endo-lysosome rupture in real-time. Our data suggest that exogenous αS can seed endogenous cytoplasmic αS by either directly penetrating the plasma membrane or via endocytosis-mediated endo-lysosome rupture, leading to formation of endo-lysosome-free or endo-lysosome-associated αS aggregates, respectively. Further, we demonstrate that αS aggregates isolated from postmortem human brains with diffuse Lewy body disease (DLBD) preferentially show endocytosis-mediated seeding associated with endo-lysosome rupture and have significantly reduced seeding activity compared to recombinant αS aggregates. Colocalization of αS pathology with galectin-3 (a marker of endo-lysosomal membrane rupture) in the basal forebrain of DLBD, but not in age-matched controls, suggests endo-lysosome rupture is involved in the formation of αS pathology in humans. Interestingly, cells with endo-lysosomal membrane permeabilization (LMP) are more vulnerable to the seeding effects of αS aggregates. This study suggests that endo-lysosomal impairment in neurons might play an important role in PD progression.Peizhou JiangMing GanShu-Hui YenPamela J. McLeanDennis W. DicksonNature 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 Peizhou Jiang Ming Gan Shu-Hui Yen Pamela J. McLean Dennis W. Dickson Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates
description	Abstract In neurodegenerative diseases, seeding is a process initiated by the internalization of exogenous protein aggregates. Multiple pathways for internalization of aggregates have been proposed, including direct membrane penetration and endocytosis. To decipher the seeding mechanisms of alpha-synuclein (αS) aggregates in human cells, we visualized αS aggregation, endo-lysosome distribution, and endo-lysosome rupture in real-time. Our data suggest that exogenous αS can seed endogenous cytoplasmic αS by either directly penetrating the plasma membrane or via endocytosis-mediated endo-lysosome rupture, leading to formation of endo-lysosome-free or endo-lysosome-associated αS aggregates, respectively. Further, we demonstrate that αS aggregates isolated from postmortem human brains with diffuse Lewy body disease (DLBD) preferentially show endocytosis-mediated seeding associated with endo-lysosome rupture and have significantly reduced seeding activity compared to recombinant αS aggregates. Colocalization of αS pathology with galectin-3 (a marker of endo-lysosomal membrane rupture) in the basal forebrain of DLBD, but not in age-matched controls, suggests endo-lysosome rupture is involved in the formation of αS pathology in humans. Interestingly, cells with endo-lysosomal membrane permeabilization (LMP) are more vulnerable to the seeding effects of αS aggregates. This study suggests that endo-lysosomal impairment in neurons might play an important role in PD progression.
format	article
author	Peizhou Jiang Ming Gan Shu-Hui Yen Pamela J. McLean Dennis W. Dickson
author_facet	Peizhou Jiang Ming Gan Shu-Hui Yen Pamela J. McLean Dennis W. Dickson
author_sort	Peizhou Jiang
title	Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates
title_short	Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates
title_full	Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates
title_fullStr	Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates
title_full_unstemmed	Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates
title_sort	impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e031185aacef45e083b20d84c1d39615
work_keys_str_mv	AT peizhoujiang impairedendolysosomalmembraneintegrityacceleratestheseedingprogressionofasynucleinaggregates AT minggan impairedendolysosomalmembraneintegrityacceleratestheseedingprogressionofasynucleinaggregates AT shuhuiyen impairedendolysosomalmembraneintegrityacceleratestheseedingprogressionofasynucleinaggregates AT pamelajmclean impairedendolysosomalmembraneintegrityacceleratestheseedingprogressionofasynucleinaggregates AT denniswdickson impairedendolysosomalmembraneintegrityacceleratestheseedingprogressionofasynucleinaggregates
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Impaired endo-lysosomal membrane integrity accelerates the seeding progression of α-synuclein aggregates

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