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

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.

• Authors: Sophie A Morgan, Isabelle Lavenir, Juan Fan, Masami Masuda-Suzukake, Daniela Passarella, Michael A DeTure, Dennis W Dickson, Bernardino Ghetti, Michel Goedert
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 19 Pg. 6652-6664 (05 08 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32209651 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Morgan et al.

Chemical References

• alpha-Synuclein

Topics

• Animals
• Brain (metabolism, pathology)
• HEK293 Cells
• Homozygote
• Humans
• Mice
• Mice, Transgenic
• Synucleinopathies (genetics, metabolism, pathology)
• alpha-Synuclein (chemistry, metabolism)