Identification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregation

authored by

Blagovesta Popova, Dan Wang, Abirami Rajavel, Karthikeyan Dhamotharan, Diana F. Lazaro, Jennifer Gerke, Joachim F. Uhrig, Michael Hoppert, Tiago F. Outeiro, Gerhard H. Braus

Abstract

Aggregation of α-synuclein (αSyn) into proteinaceous deposits is a pathological hallmark of a range of neurodegenerative diseases including Parkinson’s disease (PD). Numerous lines of evidence indicate that the accumulation of toxic oligomeric and prefibrillar αSyn species may underpin the cellular toxicity and spread of pathology between cells. Therefore, aggregation of αSyn is considered a priority target for drug development, as aggregation inhibitors are expected to reduce αSyn toxicity and serve as therapeutic agents. Here, we used the budding yeast S. cerevisiae as a platform for the identification of short peptides that inhibit αSyn aggregation and toxicity. A library consisting of approximately one million peptide variants was utilized in two high-throughput screening approaches for isolation of library representatives that reduce αSyn-associated toxicity and aggregation. Seven peptides were isolated that were able to suppress specifically αSyn toxicity and aggregation in living cells. Expression of the peptides in yeast reduced the accumulation of αSyn-induced reactive oxygen species and increased cell viability. Next, the peptides were chemically synthesized and probed for their ability to modulate αSyn aggregation in vitro. Two synthetic peptides, K84s and K102s, of 25 and 19 amino acids, respectively, significantly inhibited αSyn oligomerization and aggregation at sub-stoichiometric molar ratios. Importantly, K84s reduced αSyn aggregation in human cells. These peptides represent promising αSyn aggregation antagonists for the development of future therapeutic interventions.

External Organisation(s)

University of Göttingen
Max Planck Institute of Experimental Medicine
German Center for Neurodegenerative Diseases (DZNE)

Type

Article

Journal

Frontiers in Molecular Neuroscience

Volume

14

ISSN

1662-5099

Publication date

12.04.2021

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Cellular and Molecular Neuroscience, Molecular Biology

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.3389/fnmol.2021.659926 (Access: Open)