ArticleBiochemistry2016
Stabilization of α-Synuclein Fibril Clusters Prevents Fragmentation and Reduces Seeding Activity and Toxicity.
Article in Biochemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 41 citations in OpenAlex.
- Shifts in protein aggregate stability define proteostasis decline in the aging human brain.bioRxiv : the preprint server for biology · 2026Article
- Hydrophobic residues in the α-synuclein NAC domain drive seed-competent fibril formation and are targeted by peptide inhibitors.The FEBS journal · 2026Article
- Structural reconstruction of individual filaments in AβCommunications chemistry · 2025Article
- Article
- Review
- Pyrogallol, Corilagin and Chebulagic acid target the "fuzzy coat" of alpha-synuclein to inhibit the fibrillization of the protein.RSC advances · 2022Article
- N-Terminal Acetylation of α-Synuclein Slows down Its Aggregation Process and Alters the Morphology of the Resulting Aggregates.Biochemistry · 2022Article
- Inhibition of Polyglutamine Misfolding with D-Enantiomeric Peptides Identified by Mirror Image Phage Display Selection.Biomolecules · 2022Article
- Potent inhibitors of toxic alpha-synuclein identified via cellular time-resolved FRET biosensors.NPJ Parkinson's disease · 2021Article
- NMR unveils an N-terminal interaction interface on acetylated-α-synuclein monomers for recruitment to fibrils.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium.Journal of molecular biology · 2021Article
- Squalamine and Its Derivatives Modulate the Aggregation of Amyloid-β and α-Synuclein and Suppress the Toxicity of Their Oligomers.Frontiers in neuroscience · 2021Article
- Inhibition of protein misfolding and aggregation by natural phenolic compounds.Cellular and molecular life sciences : CMLS · 2018Review
- New Perspectives on Roles of Alpha-Synuclein in Parkinson's Disease.Frontiers in aging neuroscience · 2018Review
- Modulation of the extent of structural heterogeneity in α-synuclein fibrils by the small molecule thioflavin T.The Journal of biological chemistry · 2017Article
- High-Throughput Screening Methodology to Identify Alpha-Synuclein Aggregation Inhibitors.International journal of molecular sciences · 2017Article
- The Contribution ofNeural plasticity · 2017Review
- Neuromolecular imaging, a nanobiotechnology for Parkinson's disease: advancing pharmacotherapy for personalized medicine.Journal of neural transmission (Vienna, Austria : 1996) · 2017Article
- Protein misfolding in neurodegenerative diseases: implications and strategies.Translational neurodegeneration · 2017Review
- Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic lateral sclerosis.Acta neuropathologica · 2017Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Protein misfolding results in the accumulation of aggregated β-sheet-rich structures in Parkinson's disease (PD) and Alzheimer's disease. The toxic oligomer hypothesis stipulates that prefibrillar assemblies, such as soluble oligomers or protofibrils, are responsible for the poor prognosis of these diseases. Previous studies demonstrated that a small molecule related to the natural compound orcein, O4, directly binds to amyloid-β fibrils and stabilizes them, accelerating the formation of end-stage mature fibrils. Here we demonstrate a similar phenomenon during O4 treatment of α-synuclein (αsyn) aggregates, the protein responsible for PD pathology. While the drug did not change the kinetics of aggregate formation as measured by the amyloidophilic dye thioflavin T, O4 depleted αsyn oligomers and promoted the formation of sodium dodecyl sulfate and proteinase K resistant aggregates consisting of large fibril clusters. These fibril clusters exhibited reduced toxicity to human neuronal model cells and reduced seeding activity in vitro. The effectiveness of O4 decreased when it was added at later points in the αsyn aggregation pathway, which suggests that the incorporation of O4 into fibril assemblies stabilizes them against chemical, enzymatic, and mechanic degradation. These findings suggest that small molecules, which stabilize amyloid fibrils, can prevent fibril fragmentation and seeding and consequently prevent prion-like replication of misfolded αsyn. Inhibiting prion replication by fibril stabilization could thus be a therapeutic strategy for PD.
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