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α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species

Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cell...

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Autores principales: Morgan, Sophie A., Lavenir, Isabelle, Fan, Juan, Masuda-Suzukake, Masami, Passarella, Daniela, DeTure, Michael A., Dickson, Dennis W., Ghetti, Bernardino, Goedert, Michel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212628/
https://www.ncbi.nlm.nih.gov/pubmed/32209651
http://dx.doi.org/10.1074/jbc.RA119.012179
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author Morgan, Sophie A.
Lavenir, Isabelle
Fan, Juan
Masuda-Suzukake, Masami
Passarella, Daniela
DeTure, Michael A.
Dickson, Dennis W.
Ghetti, Bernardino
Goedert, Michel
author_facet Morgan, Sophie A.
Lavenir, Isabelle
Fan, Juan
Masuda-Suzukake, Masami
Passarella, Daniela
DeTure, Michael A.
Dickson, Dennis W.
Ghetti, Bernardino
Goedert, Michel
author_sort Morgan, Sophie A.
collection PubMed
description Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies.
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spelling pubmed-72126282020-05-18 α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species Morgan, Sophie A. Lavenir, Isabelle Fan, Juan Masuda-Suzukake, Masami Passarella, Daniela DeTure, Michael A. Dickson, Dennis W. Ghetti, Bernardino Goedert, Michel J Biol Chem Neurobiology Assembled α-synuclein in nerve cells and glial cells is the defining pathological feature of neurodegenerative diseases called synucleinopathies. Seeds of α-synuclein can induce the assembly of monomeric protein. Here, we used sucrose gradient centrifugation and transiently transfected HEK 293T cells to identify the species of α-synuclein from the brains of homozygous, symptomatic mice transgenic for human mutant A53T α-synuclein (line M83) that seed aggregation. The most potent fractions contained Sarkosyl-insoluble assemblies enriched in filaments. We also analyzed six cases of idiopathic Parkinson's disease (PD), one case of familial PD, and six cases of multiple system atrophy (MSA) for their ability to induce α-synuclein aggregation. The MSA samples were more potent than those of idiopathic PD in seeding aggregation. We found that following sucrose gradient centrifugation, the most seed-competent fractions from PD and MSA brains are those that contain Sarkosyl-insoluble α-synuclein. The fractions differed between PD and MSA, consistent with the presence of distinct conformers of assembled α-synuclein in these different samples. We conclude that α-synuclein filaments are the main driving force for amplification and propagation of pathology in synucleinopathies. American Society for Biochemistry and Molecular Biology 2020-05-08 2020-03-24 /pmc/articles/PMC7212628/ /pubmed/32209651 http://dx.doi.org/10.1074/jbc.RA119.012179 Text en © 2020 Morgan et al. Author's Choice—Final version open access under the terms of the Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) .
spellingShingle Neurobiology
Morgan, Sophie A.
Lavenir, Isabelle
Fan, Juan
Masuda-Suzukake, Masami
Passarella, Daniela
DeTure, Michael A.
Dickson, Dennis W.
Ghetti, Bernardino
Goedert, Michel
α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species
title α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species
title_full α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species
title_fullStr α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species
title_full_unstemmed α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species
title_short α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species
title_sort α-synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species
topic Neurobiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212628/
https://www.ncbi.nlm.nih.gov/pubmed/32209651
http://dx.doi.org/10.1074/jbc.RA119.012179
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