Remodeling of the Fibrillation Pathway of α‐Synuclein by Interaction with Antimicrobial Peptide LL‐III

Oliva, Rosario; Mukherjee, Sumitava; Ostermeier, Lena; Pazurek, Lilli A.; Kriegler, Simon; Bader, Verian; Prumbaum, Daniel; Raunser, Stefan; Winklhofer, Konstanze F.; Tatzelt, Jörg; Winter, Roland

doi:10.1002/chem.202101592

Cited by 17 publications

(16 citation statements)

References 35 publications

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“…Actually, a few recent studies have reported that the LLPS of amyloid proteins could be regulated by small molecules or peptides, which further affect its amyloid aggregation. For example, LL‐III, a kind of antimicrobial peptide extracted from the venom of the eusocial bee, was reported to stabilize α‐Syn droplets and prevent the conversion of α‐Syn to the fibrillar state [60] . Another study reported that C 1 , a synthetic derivative of curcumin, could reduce the size and number of the Tau protein droplets to inhibit Tau protein‘s amyloid aggregation strongly [61] .…”

Section: Discussionmentioning

confidence: 99%

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Chen

et al. 2022

ChemBioChem

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The aggregation of α-synuclein (α-Syn) is a critical pathological hallmark of Parkinson's disease (PD). Prevention of α-Syn aggregation has become a key strategy for treating PD. Recent studies have suggested that α-Syn undergoes liquid-liquid phase separation (LLPS) to facilitate nucleation and amyloid formation. Here, we examined the modulation of α-Syn aggregation by myricetin, a polyhydroxyflavonol compound, under the conditions of LLPS. Unexpectedly, neither the initial morphology nor the phase-separated fraction of α-Syn was altered by myricetin. However, the dynamics of α-Syn con-densates decreased upon myricetin binding. Further studies showed that myricetin dose-dependently inhibits amyloid aggregation in the condensates by delaying the liquid-to-solid phase transition. In addition, myricetin could disassemble the preformed α-Syn amyloid aggregates matured from the condensates. Together, our study shows that myricetin inhibits α-Syn amyloid aggregation in the condensates by retarding the liquid-to-solid phase transition and reveals that α-Syn phase transition can be targeted to inhibit amyloid aggregation. www.chembiochem.org

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Section: Discussionmentioning

confidence: 99%

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Chen

et al. 2022

ChemBioChem

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“…These receptors may have less affinity to the α-Syn conformers formed in the presence of Zn 2+ compared to the other types of fibrils used in the current study. Alternatively, polymorphically different fibrils could have different seeding activities once entered the cells 36 . According to our unpublished data, the polymorphically different fibrils formed in the presence of various cations can imprint their morphology in the newly formed fibrils.…”

Section: Discussionmentioning

confidence: 99%

Bivalent metal ions induce formation of α-synuclein fibril polymorphs with different cytotoxicities

Atarod

Mamashli

Ghasemi

et al. 2022

Sci Rep

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Abstractα-Synuclein (α-Syn) aggregates are key components of intracellular inclusion bodies characteristic of Parkinson’s disease (PD) and other synucleinopathies. Metal ions have been considered as the important etiological factors in PD since their interactions with α-Syn alter the kinetics of fibrillation. In the present study, we have systematically explored the effects of Zn2+, Cu2+, Ca2+, and Mg2+ cations on α-Syn fibril formation. Specifically, we determined fibrillation kinetics, size, morphology, and secondary structure of the fibrils and their cytotoxic activity. While all cations accelerate fibrillation, we observed distinct effects of the different ions. For example, Zn2+ induced fibrillation by lower tlag and higher kapp and formation of shorter fibrils, while Ca2+ ions lead to formation of longer fibrils, as evidenced by dynamic light scattering and atomic force microscopy studies. Additionally, the morphology of formed fibrils was different. Circular dichroism and attenuated total reflection-Fourier transform infrared spectroscopies revealed higher contents of β-sheets in fibrils. Interestingly, cell viability studies indicated nontoxicity of α-Syn fibrils formed in the presence of Zn2+ ions, while the fibrils formed in the presence of Cu2+, Ca2+, and Mg2+ were cytotoxic. Our results revealed that α-Syn fibrils formed in the presence of different divalent cations have distinct structural and cytotoxic features.

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“…This along with the fact that there are a number of receptors at the cell membrane, which bind to β-sheet rich conformers such as cellular prion protein 36 , led us to the hypothesis that maybe there are speci c receptors at the cell surface for particular types of α-Syn oligomers, whose activation upon binding of the oligomers can transduce various deadly or survival intracellular cell signals. Alternatively, polymorphically different brils could have different seeding activities once entered the cells 37 . Therefore, the authors suggest that the type of β-sheet formed in brils can affect the interactions of brils with the potential receptors at the cell surface and consequently their cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Various metal ions promote formation of α-Synuclein fibrils with different shapes and cytotoxicities.

Saboury

Atarod

Mamashli

et al. 2022

Preprint

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α-Synuclein (α-Syn) aggregates are key components of intracellular inclusion bodies characteristic of Parkinson’s disease (PD) and other synucleinopathies. Metal ions have been considered as the important etiological factors in PD since their interactions with α-Syn alter the kinetics of fibrillation. In the present study, we have systematically explored the effects of Zn2+, Cu2+, Ca2+, and Mg2+ cations on α-Syn fibril formation. Specifically, we determined fibrillation kinetics, size, morphology, and secondary structure of the fibrils and their cytotoxic activity. While all cations accelerate fibrillation we observed distinct effects of the different ions. For example, Zn2+ induced fibrillation by lower tlag and higher kapp and formation of shorter fibrils, while Ca2+ ions lead to formation of longer fibrils, evidences by dynamic light scattering and atomic force microscopy studies. Additionally, the morphology of formed fibrils was different. Circular dichroism studies revealed higher content of antiparallel β-sheets in fibrils formed in the presence of Zn2+. Interestingly, cell viability studies indicated nontoxicity of α-Syn fibrils formed in the presence of Zn2+ ions, while the fibrils formed in the presence of Cu2+, Ca2+, and Mg2+ were cytotoxic. Our results revealed that α-Syn fibrils formed in the presence of different divalent cations have distinct structural and cytotoxic features and indicate a protective role of Zn2+ in the formation of neurotoxic α-Syn assemblies.

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Remodeling of the Fibrillation Pathway of α‐Synuclein by Interaction with Antimicrobial Peptide LL‐III

Cited by 17 publications

References 35 publications

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Myricetin Inhibits α‐Synuclein Amyloid Aggregation by Delaying the Liquid‐to‐Solid Phase Transition

Bivalent metal ions induce formation of α-synuclein fibril polymorphs with different cytotoxicities

Various metal ions promote formation of α-Synuclein fibrils with different shapes and cytotoxicities.

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