A study on the interaction of the amyloid fibrils of α-synuclein and hen egg white lysozyme with biological membranes

Zadali, Ramin; Hassani, Vahid; Rafiei, Yasin; Meratan, Ali Akbar; Mamashli, Fatemeh; Nemat‐Gorgani, Mohsen

doi:10.1016/j.bbamem.2021.183776

Cited by 12 publications

(16 citation statements)

References 77 publications

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“…It has been shown that α-Syn brils can bind plasma membranes of neuronal cells and induce cell death 33 . We observed cytotoxicity of α-Syn brils formed in absence of metal ions, which was comparable to the published reports 22,23 . Enhanced cytotoxicity of α-Syn brils formed in presence of Cu 2+ has also been reported 24 .…”

Section: Discussionsupporting

confidence: 92%

“…It was interesting to note that 10 or 20 µM of brils formed in presence of Zn 2+ did not change cell viability. However, brils of the control sample and brils formed in presence of Cu 2+ , Ca 2+ , and Mg 2+ led to signi cant decrease in cell viability at both tested concentrations, what remains in agreement with earlier published reports [22][23][24] . We also checked the cytotoxicity of the studied cations at the concentration the cells receive when treated with α-Syn brils and detected no toxicity (data not shown).…”

Section: Various Metal Ions Induced Formation Of Different αSynuclein...supporting

confidence: 92%

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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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Section: Discussionsupporting

confidence: 92%

Section: Various Metal Ions Induced Formation Of Different αSynuclein...supporting

confidence: 92%

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

Saboury

Atarod

Mamashli

et al. 2022

Preprint

Self Cite

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“…According to previous studies, α-Syn fibrils released from dead neurons into extracellular space can be cytotoxic to neighboring neurons 33 . We observed cytotoxicity of α-Syn fibrils formed in the absence of metal ions, which was comparable to the published reports 26 , 27 . We also observed higher cytotoxicity of α-Syn fibrils formed in the presence of Cu 2+ , Ca 2+ and Mg 2+ .…”

Section: Discussionsupporting

confidence: 92%

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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“…Indeed, as previously mentioned, the main advantage of Doxy is that it has a safe pharmacological pro le and easily crosses the blood brain barrier as determined through pharmacokinetic studies at preclinical level [22]. In addition, its administration at sub-antimicrobial doses does not trigger the acquisition of pharmacological resistances in bacteria [15].…”

Section: Discussionmentioning

confidence: 99%

“…Neuroin ammation and intraneuronal inclusions, mainly composed by alpha-synuclein (α-syn), are both culprits and neuropathological hallmarks of PD and its related disorders. From an etiological standpoint, α-syn oligomeric assemblies (α-synO) are recognized as the main neurotoxic moieties capable of causing cognitive de cits, long term potentiation (LTP) impairment, in ammation, synaptic damage and neuronal loss [2][3][4][5][6][7][8][9][10][11], although other conformers might exerted similar neurotoxic activity [12][13][14][15]. We hypothesized that a therapeutic approach based on a single molecule affecting at the same time α-syn aggregation and neuroin ammation may offer a promising tool to alleviate PD progression.…”

Section: Introductionmentioning

confidence: 99%

Repositioning doxycycline for treating Parkinson’s disease: Evidence from a pre‐clinical mouse model

Vitola

Artioli

Cerovic

et al. 2021

Alzheimer's & Dementia

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Background: Parkinson's disease (PD) is a neurodegenerative disorder orphan of valuable therapies. PD is neuropathological characterized by intracellular Lewy bodies formed by aggregated α-synuclein (α-syn ) in mesencephalic region and neuroinflammation significantly contribute to the pathogenesis of the disease. In the complex scenario of PD single target therapy cannot be beneficial, a therapeutic strategy simultaneously affecting α-syn aggregation and neuroinflammation may be useful to affect PD progression. Recently, the antimicrobial drug Doxycycline (Doxy) has been demonstrated to inhibit α-syn aggregation. In addition, we have reported that Doxy at subantibiotic doses efficiently counteracts memory impairment and neuroinflammation in a transgenic (Tg) mouse model of Alzheimer's Disease. Based on the multiple action mechanism of Doxy, we herein investigate the potential therapeutic properties of Doxy in a Tg PD mouse model. Method: A53T mice and their non-Tg (NTG) litter mates were intraperitoneally treated with 10mg/Kg Doxy for 30 days. At the end of treatment, cognitive and motor performances were evaluated in the Novel object recognition test (NORT), Nesting test, Beam-walk and Paw grip endurance. In addition, hippocampal long term potentiation (LTP) was assessed. Neuropathological markers were explored through immunohistological and biochemical approaches.Result: Doxy abolished the cognitive deficit in the NORT. Moreover, Doxy restored daily life activity of A53T mice in the Nesting test, which is dependent by hippocampal and cortical networks. Aside from an effect at cognitive level, we found that Doxy treatment ameliorated motor performances in both the Beam-walk test and in the Paw grip endurance. The effect on cognitive functions was strictly linked to a reduced neuronal loss in the cortex and hippocampus of A53T+Doxy compared to A53T+Veh group. Moreover, glial activation were blocked by our pharmacological approach both in the cortex and hippocampus. In addition, Doxy treatment restored hippocampal LTP in association with the dampening of pro-inflammatory cytokines expression. Conclusion:Doxy emerges as a valuable therapeutic approach to counteract both symptoms and neuropathological hallmarks in the complex scenario of a Tg PD mouse model. Moreover, our results depict PD as a novel field for repurposing Doxy and corroborate previous data indicating Doxy as a multi-target drug.

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A study on the interaction of the amyloid fibrils of α-synuclein and hen egg white lysozyme with biological membranes

Cited by 12 publications

References 77 publications

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

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

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

Repositioning doxycycline for treating Parkinson’s disease: Evidence from a pre‐clinical mouse model

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