Real-Time Characterization of Cell Membrane Disruption by α-Synuclein Oligomers in Live SH-SY5Y Neuroblastoma Cells

Parres-Gold, Jacob; Chieng, Andy; Su, Stephanie Wong; Wang, Yixian

doi:10.1021/acschemneuro.0c00309

Cited by 15 publications

(18 citation statements)

References 36 publications

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“…Kim et al [22] also found that α-Syn oligomers formed well-defined conductance states in a variety of membranes and that the beta-structure of these membrane-bound oligomers differed from that of α-Syn fibrils. Parres-Gold et al [24] used scanning ion conductance microscopy (SICM) to show that α-Syn oligomers induce morphological changes and formation of large transient pores in live SH-SY5Y neuroblastoma cells. Toxic α-Syn accumulation in SH-SY5Y is alleviated by membrane depolarization [62], suggesting that membrane interactions of α-Syn are related to toxicity in these cells.…”

Section: Equilibrium Among Type 2 Oligomers Protofibrils and Fibrilsmentioning

confidence: 99%

See 1 more Smart Citation

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

Durell

Guy²

2021

Preprint

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Amyloid beta (Aβ of Alzheimers disease) and α-synuclein (α-Syn of Parkinsons disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aβ42 oligomers, annular protofibrils, and ion channels adopt concentric β-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, β, and γ-synucleins. Our models of numerous Synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by EM and other studies. The models have the following features: 1) all subunits have identical structures and interactions; 2) they are consistent with conventional β-barrel theory; 3) the distance between walls of adjacent β-barrels is between 0.6 and 1.2 nm; 4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and 5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.

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Section: Equilibrium Among Type 2 Oligomers Protofibrils and Fibrilsmentioning

confidence: 99%

“…Eichmann et al [19] have published EM images of high-density lipoproteins formed by all three families of synucleins in the presence of sphingomyelin. Also, numerous studies have found that α-Syn permeabilizes membranes and forms channels in both artificial membranes [20–23], and neural cells [24–26].…”

Section: Introductionmentioning

confidence: 99%

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

Durell

Guy²

2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Kim et al [22] also found that α-Syn oligomers formed well-defined conductance states in a variety of membranes and that the beta-structure of these membranebound oligomers differed from that of α-Syn fibrils. Parres-Gold et al [24] used scanning ion conductance microscopy (SICM) to show that α-Syn oligomers induce morphological changes and formation of large transient pores in live SH-SY5Y neuroblastoma cells. Toxic α-Syn accumulation in SH-SY5Y is alleviated by membrane depolarization [62], suggesting that membrane interactions of α-Syn are related to toxicity in these cells.…”

Section: ηιγη δενσιτψ λιποπροτεινς: γ-σψνmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels.

Durell²

2021

Preprint

View full text Add to dashboard Cite

Amyloid beta (Aβ of Alzheimer’s disease) and α-synuclein (α-Syn of Parkinson’s disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aβ42 oligomers, annular protofibrils, and ion channels adopt concentric β-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, β, and γ-synucleins. Our models of numerous Synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by EM and other studies. The models have the following features: 1) all subunits have identical structures and interactions; 2) they are consistent with conventional β-barrel theory; 3) the distance between walls of adjacent β-barrels is between 0.6 and 1.2 nm; 4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and 5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.

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“…Also, numerous studies have found that α-Syn permeabilizes membranes and forms channels in both artificial membranes [20][21][22][23] and neural cells. [24][25][26] Several familial mutations that contribute to PD have been identified, most of which are sequentially near each other. However, it is unclear how or whether these alter oligomer conformations or the binding of this segment into a cleft within the Cyclophilin A protein.…”

mentioning

confidence: 99%

The amyloid concentric β‐barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

Durell

H²

2021

Proteins

View full text Add to dashboard Cite

Amyloid beta (Aβ of Alzheimer's disease) and α-synuclein (α-Syn of Parkinson's disease) form large fibrils. Evidence is increasing however that much smaller oligomers are more toxic and that these oligomers can form transmembrane ion channels. We have proposed previously that Aβ42 oligomers, annular protofibrils, and ion channels adopt concentric β-barrel molecular structures. Here we extend that hypothesis to the superfamily of α, β, and γ-synucleins. Our models of numerous synuclein oligomers, annular protofibrils, tubular protofibrils, lipoproteins, and ion channels were developed to be consistent with sizes, shapes, molecular weights, and secondary structures of assemblies as determined by electron microscopy and other studies.The models have the following features: (1) all subunits have identical structures and interactions; (2) they are consistent with conventional β-barrel theory; (3) the distance between walls of adjacent β-barrels is between 0.6 and 1.2 nm; (4) hydrogen bonds, salt bridges, interactions among aromatic side-chains, burial and tight packing of hydrophobic side-chains, and aqueous solvent exposure of hydrophilic side-chains are relatively optimal; and (5) residues that are identical among distantly related homologous proteins cluster in the interior of most oligomers whereas residues that are hypervariable are exposed on protein surfaces. Atomic scale models of some assemblies were developed.

show abstract

Real-Time Characterization of Cell Membrane Disruption by α-Synuclein Oligomers in Live SH-SY5Y Neuroblastoma Cells

Cited by 15 publications

References 36 publications

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

The amyloid concentric β-barrel hypothesis: models of Synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels.

The amyloid concentric β‐barrel hypothesis: Models of synuclein oligomers, annular protofibrils, lipoproteins, and transmembrane channels

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