Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro

Abstract Lewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation...

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Autores principales:	Nicholas P. Marotta, Jahan Ara, Norihito Uemura, Marshall G. Lougee, Emily S. Meymand, Bin Zhang, E. James Petersson, John Q. Trojanowski, Virginia M.-Y. Lee
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/bf7a534148ef4b5692dfe56fe3d96872
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spelling	oai:doaj.org-article:bf7a534148ef4b5692dfe56fe3d968722021-11-28T12:09:12ZAlpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro10.1186/s40478-021-01288-22051-5960https://doaj.org/article/bf7a534148ef4b5692dfe56fe3d968722021-11-01T00:00:00Zhttps://doi.org/10.1186/s40478-021-01288-2https://doaj.org/toc/2051-5960Abstract Lewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases. These α-Syn PFFs recapitulate many pathological phenotypes in both cultured cells and animal models including the formation of α-Syn rich, insoluble aggregates, neuron loss, and motor deficits. However, it is not clear how closely α-Syn PFFs recapitulate the biological behavior of LB aggregates isolated directly from patients. Direct interrogation of the cellular response to LB-derived α-Syn has thus far been limited. Here we demonstrate that α-Syn aggregates derived from LB disease patients induce pathology characterized by a prevalence of large somatic inclusions that is distinct from the primarily neuritic pathology induced by α-Syn PFFs in our cultured neuron model. Moreover, these LB-derived aggregates can be amplified in vitro using recombinant α-Syn to generate aggregates that maintain the unique, somatic pathological phenotype of the original material. Amplified LB aggregates also showed greater uptake in cultured neurons and greater pathological burden and more rapid pathological spread in injected mouse brains, compared to α-Syn PFFs. Our work indicates that LB-derived α-Syn from diseased brains represents a distinct conformation species with unique biological activities that has not been previously observed in fully recombinant α-Syn aggregates and demonstrate a new strategy for improving upon α-Syn PFF models of synucleinopathies using amplified LBs.Nicholas P. MarottaJahan AraNorihito UemuraMarshall G. LougeeEmily S. MeymandBin ZhangE. James PeterssonJohn Q. TrojanowskiVirginia M.-Y. LeeBMCarticleNeurology. Diseases of the nervous systemRC346-429ENActa Neuropathologica Communications, Vol 9, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurology. Diseases of the nervous system RC346-429 Nicholas P. Marotta Jahan Ara Norihito Uemura Marshall G. Lougee Emily S. Meymand Bin Zhang E. James Petersson John Q. Trojanowski Virginia M.-Y. Lee Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro
description	Abstract Lewy bodies (LBs) are complex, intracellular inclusions that are common pathological features of many neurodegenerative diseases. They consist largely of aggregated forms of the protein alpha-Synuclein (α-Syn), which misfolds to give rise to beta-sheet rich amyloid fibrils. The aggregation of monomers into fibrils occurs readily in vitro and pre-formed fibrils (PFFs) generated from recombinant α-Syn monomers are the basis of many models of LB diseases. These α-Syn PFFs recapitulate many pathological phenotypes in both cultured cells and animal models including the formation of α-Syn rich, insoluble aggregates, neuron loss, and motor deficits. However, it is not clear how closely α-Syn PFFs recapitulate the biological behavior of LB aggregates isolated directly from patients. Direct interrogation of the cellular response to LB-derived α-Syn has thus far been limited. Here we demonstrate that α-Syn aggregates derived from LB disease patients induce pathology characterized by a prevalence of large somatic inclusions that is distinct from the primarily neuritic pathology induced by α-Syn PFFs in our cultured neuron model. Moreover, these LB-derived aggregates can be amplified in vitro using recombinant α-Syn to generate aggregates that maintain the unique, somatic pathological phenotype of the original material. Amplified LB aggregates also showed greater uptake in cultured neurons and greater pathological burden and more rapid pathological spread in injected mouse brains, compared to α-Syn PFFs. Our work indicates that LB-derived α-Syn from diseased brains represents a distinct conformation species with unique biological activities that has not been previously observed in fully recombinant α-Syn aggregates and demonstrate a new strategy for improving upon α-Syn PFF models of synucleinopathies using amplified LBs.
format	article
author	Nicholas P. Marotta Jahan Ara Norihito Uemura Marshall G. Lougee Emily S. Meymand Bin Zhang E. James Petersson John Q. Trojanowski Virginia M.-Y. Lee
author_facet	Nicholas P. Marotta Jahan Ara Norihito Uemura Marshall G. Lougee Emily S. Meymand Bin Zhang E. James Petersson John Q. Trojanowski Virginia M.-Y. Lee
author_sort	Nicholas P. Marotta
title	Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro
title_short	Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro
title_full	Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro
title_fullStr	Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro
title_full_unstemmed	Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro
title_sort	alpha-synuclein from patient lewy bodies exhibits distinct pathological activity that can be propagated in vitro
publisher	BMC
publishDate	2021
url	https://doaj.org/article/bf7a534148ef4b5692dfe56fe3d96872
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Alpha-synuclein from patient Lewy bodies exhibits distinct pathological activity that can be propagated in vitro

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