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Dr. Mantas Žiaunys

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Sector of Amyloid Research, Institute of Biotechnology, Life Sciences Center, Vilnius University, Saulėtekio 7, 10257 Vilnius, Lithuania
Interests: amyloid fibril; protein aggregation; secondary structure; β-sheet; amide II; amyloids; prion proteins; fibril structure; s100a9; synuclein; amyloid proteins; fibrils; FTIR; AFM

Special Issue Information

Dear Colleagues,

Alpha-synuclein is linked with multiple neurodegenerative disorders, including Parkinson‘s disease, dementia with Lewy bodies, and multiple-system atrophy. It is also known to be associated with amyloid plaques found in patients suffering from Alzheimer‘s disease. Investigations into the subject of alpha-synuclein amyloid aggregation have demonstrated the protein’s ability to form multiple structurally diverse fibril strains and suggested their link with distinct synucleinopathies. These alpha-synuclein strains carry diverse levels of seeding, propagation, and neurotoxicity potential. Therefore, an immense amount of effort has been dedicated towards deciphering the underlying factors which determine this prion-like structural variability, including genetic mutations, environmental conditions, co-interactions with other proteins, and the recent discovery of liquid–liquid phase separation of alpha-synuclein. Despite tremendous progress in this field, there are still various unknown or unexplored factors regarding the transition from native state alpha-synuclein to its pathogenic variants. The purpose of this Special Issue is to collect scientific articles and reviews that can provide new molecular perspectives in the field of alpha-synuclein amyloid fibril formation.

Dr. Mantas Žiaunys
Guest Editor

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Keywords

alpha-synuclein
amyloid
protein aggregation
synucleinopathies
protein fibrils
protein misfolding
prion-like
protein-protein interactions

Published Papers (2 papers)

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Research

19 pages, 2790 KiB

Open AccessArticle

Biochemical Fractionation of Human α-Synuclein in a Drosophila Model of Synucleinopathies

by Khondamir Imomnazarov, Joshua Lopez-Scarim, Ila Bagheri, Valerie Joers, Malú Gámez Tansey and Alfonso Martín-Peña

Int. J. Mol. Sci. 2024, 25(7), 3643; https://doi.org/10.3390/ijms25073643 - 25 Mar 2024

Viewed by 642

Abstract

Synucleinopathies are a group of central nervous system pathologies that are characterized by the intracellular accumulation of misfolded and aggregated α-synuclein in proteinaceous depositions known as Lewy Bodies (LBs). The transition of α-synuclein from its physiological to pathological form has been associated with several post-translational modifications such as phosphorylation and an increasing degree of insolubility, which also correlate with disease progression in post-mortem specimens from human patients. Neuronal expression of α-synuclein in model organisms, including Drosophila melanogaster, has been a typical approach employed to study its physiological effects. Biochemical analysis of α-synuclein solubility via high-speed ultracentrifugation with buffers of increasing detergent strength offers a potent method for identification of α-synuclein biochemical properties and the associated pathology stage. Unfortunately, the development of a robust and reproducible method for the evaluation of human α-synuclein solubility isolated from Drosophila tissues has remained elusive. Here, we tested different detergents for their ability to solubilize human α-synuclein carrying the pathological mutation A53T from the brains of aged flies. We also assessed the effect of sonication on the solubility of human α-synuclein and optimized a protocol to discriminate the relative amounts of soluble/insoluble human α-synuclein from dopaminergic neurons of the Drosophila brain. Our data established that, using a 5% SDS buffer, the three-step protocol separates cytosolic soluble, detergent-soluble and insoluble proteins in three sequential fractions according to their chemical properties. This protocol shows that sonication breaks down α-synuclein insoluble complexes from the fly brain, making them soluble in the SDS buffer and thus enriching the detergent-soluble fraction of the protocol. Full article

(This article belongs to the Special Issue Alpha-Synuclein Amyloid Fibril Formation: New Molecular Perspectives)

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14 pages, 10519 KiB

Open AccessArticle

Nucleation of α-Synuclein Amyloid Fibrils Induced by Cross-Interaction with β-Hairpin Peptides Derived from Immunoglobulin Light Chains

by Laetitia F. Heid, Tatsiana Kupreichyk, Marie P. Schützmann, Walfried Schneider, Matthias Stoldt and Wolfgang Hoyer

Int. J. Mol. Sci. 2023, 24(22), 16132; https://doi.org/10.3390/ijms242216132 - 09 Nov 2023

Viewed by 962

Abstract

Heterologous interactions between different amyloid-forming proteins, also called cross-interactions, may have a critical impact on disease-related amyloid formation. β-hairpin conformers of amyloid-forming proteins have been shown to affect homologous interactions in the amyloid self-assembly process. Here, we applied two β-hairpin-forming peptides derived from immunoglobulin light chains as models to test how heterologous β-hairpins modulate the fibril formation of Parkinson’s disease-associated protein α-synuclein (αSyn). The peptides SMAhp and LENhp comprise β-strands C and C′ of the κ4 antibodies SMA and LEN, which are associated with light chain amyloidosis and multiple myeloma, respectively. SMAhp and LENhp bind with high affinity to the β-hairpin-binding protein β-wrapin AS10 according to isothermal titration calorimetry and NMR spectroscopy. The addition of SMAhp and LENhp affects the kinetics of αSyn aggregation monitored by Thioflavin T (ThT) fluorescence, with the effect depending on assay conditions, salt concentration, and the applied β-hairpin peptide. In the absence of agitation, substoichiometric concentrations of the hairpin peptides strongly reduce the lag time of αSyn aggregation, suggesting that they support the nucleation of αSyn amyloid fibrils. The effect is also observed for the aggregation of αSyn fragments lacking the N-terminus or the C-terminus, indicating that the promotion of nucleation involves the interaction of hairpin peptides with the hydrophobic non-amyloid-β component (NAC) region. Full article

(This article belongs to the Special Issue Alpha-Synuclein Amyloid Fibril Formation: New Molecular Perspectives)

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Alpha-Synuclein Amyloid Fibril Formation: New Molecular Perspectives

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