Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

Breadcrumb Navigation


Alpha-synuclein fragments trigger distinct aggregation pathways

Cell Death Dis. 2020 Feb 3;11(2):84

Authors/Editors: Tasnim Chakroun
Valentin Evsyukov
Niko-Petteri Nykänen
Matthias Höllerhage
Andreas Schmidt
Frits Kamp
Viktoria C Ruf
Wolfgang Wurst
Thomas W Rösler
Günter U Höglinger
Publication Date: 2020
Type of Publication: Journal Article

Aggregation of alpha-synuclein (αSyn) is a crucial event underlying the pathophysiology of synucleinopathies. The existence of various intracellular and extracellular αSyn species, including cleaved αSyn, complicates the quest for an appropriate therapeutic target. Hence, to develop efficient disease-modifying strategies, it is fundamental to achieve a deeper understanding of the relevant spreading and toxic αSyn species. Here, we describe comparative and proof-of-principle approaches to determine the involvement of αSyn fragments in intercellular spreading. We demonstrate that two different αSyn fragments (1-95 and 61-140) fulfill the criteria of spreading species. They efficiently instigate formation of proteinase-K-resistant aggregates from cell-endogenous full-length αSyn, and drive it into different aggregation pathways. The resulting aggregates induce cellular toxicity. Strikingly, these aggregates are only detectable by specific antibodies. Our results suggest that αSyn fragments might be relevant not only for spreading, but also for aggregation-fate determination and differential strain formation.

Related Links