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

Sophie A. Morgan, Isabelle Lavenir, Juan Fan, Masami Masuda-Suzukake, Daniela Passarella, Michael A. DeTure, Dennis W. Dickson, X. Bernardino Ghetti, Michel Goedert

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6652-6664
Number of pages13
JournalJournal of Biological Chemistry
Volume295
Issue number19
DOIs
StatePublished - May 8 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species'. Together they form a unique fingerprint.

  • Cite this

    Morgan, S. A., Lavenir, I., Fan, J., Masuda-Suzukake, M., Passarella, D., DeTure, M. A., Dickson, D. W., Bernardino Ghetti, X., & Goedert, M. (2020). α-Synuclein filaments from transgenic mouse and human synucleinopathy-containing brains are major seed-competent species. Journal of Biological Chemistry, 295(19), 6652-6664. https://doi.org/10.1074/jbc.RA119.012179