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The effect of truncation on prion-like properties of α-synuclein.


ABSTRACT: Increasing evidence suggests that α-synuclein (αS) aggregates in brains of individuals with Parkinson's disease and dementia with Lewy bodies can spread in a prion-like manner. Although the initial αS nuclei are pivotal in determining αS fibril polymorphs and resulting phenotypes, it is not clear how the initial fibril seeds are generated. Previous studies have shown that αS truncation might have an important role in αS aggregation. However, little is known about how this truncation influences αS's propagation properties. In the present study, we generated αS fibrils from a series of truncated human αS constructs, characterized their structures and conformational stabilities, and investigated their ability to convert the conformation of full-length αS in vitro, in cultured cells, and in WT mice. We show that both C- and N-terminal truncations of human αS induce fibril polymorphs and exhibit different cross-seeding activities. N-terminally 10- or 30-residue-truncated human αS fibrils induced more abundant αS pathologies than WT fibrils in mice, whereas other truncated fibrils induced less abundant pathologies. Biochemical analyses of these truncated fibrils revealed that N-terminal 10- or 30-residue truncations of human αS change the fibril conformation in a manner that increases their structural compatibility with WT mouse αS fibrils and reduces their stability. C-terminally 20-residue-truncated fibrils displayed enhanced seeding activity in vitro Our findings imply that truncation of αS can influence its prion-like pathogenicity, resulting in phenotypic diversity of α-synucleinopathies.

SUBMITTER: Terada M 

PROVIDER: S-EPMC6130941 | biostudies-literature |

REPOSITORIES: biostudies-literature

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