Details
| Originalsprache | Englisch |
|---|---|
| Aufsatznummer | 659926 |
| Fachzeitschrift | Frontiers in Molecular Neuroscience |
| Jahrgang | 14 |
| Publikationsstatus | Veröffentlicht - 12 Apr. 2021 |
| Extern publiziert | Ja |
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.
ASJC Scopus Sachgebiete
- Neurowissenschaften (insg.)
- Zelluläre und Molekulare Neurowissenschaften
- Biochemie, Genetik und Molekularbiologie (insg.)
- Molekularbiologie
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in: Frontiers in Molecular Neuroscience, Jahrgang 14, 659926, 12.04.2021.
Publikation: Beitrag in Fachzeitschrift › Artikel › Forschung › Peer-Review
}
TY - JOUR
T1 - Identification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregation
AU - Popova, Blagovesta
AU - Wang, Dan
AU - Rajavel, Abirami
AU - Dhamotharan, Karthikeyan
AU - Lazaro, Diana F.
AU - Gerke, Jennifer
AU - Uhrig, Joachim F.
AU - Hoppert, Michael
AU - Outeiro, Tiago F.
AU - Braus, Gerhard H.
N1 - Funding information: This work was supported by Deutsche Forschungsgemeinschaft (DFG: BR 1502/18-1 to GB). DW was supported by China Scholarship Council (CSC No. 201706760021). TO was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2067/1-390729940).
PY - 2021/4/12
Y1 - 2021/4/12
N2 - 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.
AB - 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.
KW - α
KW - -synuclein
KW - Parkinson’
KW - s disease
KW - protein aggregation
KW - oligomerization
KW - peptide drug discovery
KW - yeast
KW - library screening
KW - Parkinson’s disease
KW - α-synuclein
UR - http://www.scopus.com/inward/record.url?scp=85104976955&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2021.659926
DO - 10.3389/fnmol.2021.659926
M3 - Article
VL - 14
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
SN - 1662-5099
M1 - 659926
ER -