α-synucleins from animal species show low fibrillation propensities and weak oligomer membrane disruption

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α-synucleins from animal species show low fibrillation propensities and weak oligomer membrane disruption. / Sahin, Cagla; Kjær, Lars; Christensen, Mette Solvang; Nedergaard Pedersen, Jannik; Christiansen, Gunna; Pérez, Adriana-Michelle Wolf; Moller, Ian Max; Enghild, Jan; Pedersen, Jan Skov; Larsen, Knud; Otzen, Daniel Erik.

In: Biochemistry, Vol. 57, No. 34, 2018, p. 5145-5158.

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@article{20378782108646bfb33e481ce1b85f0d,
title = "α-synucleins from animal species show low fibrillation propensities and weak oligomer membrane disruption",
abstract = "The intrinsically disordered protein α-synuclein (aSN) forms insoluble aggregates in the brains of Parkinson's Disease patients. Cytotoxicity is attributed to a soluble aSN oligomeric species which permeabilizes membranes significantly more than monomers and fibrils. In humans, the mutation A53T induces early-onset PD and increases aSN oligomerization and fibrillation propensity, but Thr53 occurs naturally in aSN of most animals. We compared aSN from elephant, bowhead whale and pig with human aSN. While all three animal aSN showed significantly reduced fibrillation behavior, elephant aSN formed much more oligomer, and pig aSN much less, than human aSN. However, all animal aSN oligomers showed decreased permeabilization towards anionic lipid vesicles, indicative of lowered cytotoxicity. These animal aSN share three substitutions compared to human aSN: A53T, G68E and V95G. We analyzed aggregation and membrane binding of all 8 mutants combining these three mutations. While G68E is particularly important in reducing the fibrillation and possible toxicity, the greatest effect is seen when all three mutations are present. Thus a small number of mutations can significantly reduce aSN toxicity.",
author = "Cagla Sahin and Lars Kj{\ae}r and Christensen, {Mette Solvang} and {Nedergaard Pedersen}, Jannik and Gunna Christiansen and P{\'e}rez, {Adriana-Michelle Wolf} and Moller, {Ian Max} and Jan Enghild and Pedersen, {Jan Skov} and Knud Larsen and Otzen, {Daniel Erik}",
year = "2018",
doi = "10.1021/acs.biochem.8b00627",
language = "English",
volume = "57",
pages = "5145--5158",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "ACS Publications",
number = "34",

}

RIS

TY - JOUR

T1 - α-synucleins from animal species show low fibrillation propensities and weak oligomer membrane disruption

AU - Sahin, Cagla

AU - Kjær, Lars

AU - Christensen, Mette Solvang

AU - Nedergaard Pedersen, Jannik

AU - Christiansen, Gunna

AU - Pérez, Adriana-Michelle Wolf

AU - Moller, Ian Max

AU - Enghild, Jan

AU - Pedersen, Jan Skov

AU - Larsen, Knud

AU - Otzen, Daniel Erik

PY - 2018

Y1 - 2018

N2 - The intrinsically disordered protein α-synuclein (aSN) forms insoluble aggregates in the brains of Parkinson's Disease patients. Cytotoxicity is attributed to a soluble aSN oligomeric species which permeabilizes membranes significantly more than monomers and fibrils. In humans, the mutation A53T induces early-onset PD and increases aSN oligomerization and fibrillation propensity, but Thr53 occurs naturally in aSN of most animals. We compared aSN from elephant, bowhead whale and pig with human aSN. While all three animal aSN showed significantly reduced fibrillation behavior, elephant aSN formed much more oligomer, and pig aSN much less, than human aSN. However, all animal aSN oligomers showed decreased permeabilization towards anionic lipid vesicles, indicative of lowered cytotoxicity. These animal aSN share three substitutions compared to human aSN: A53T, G68E and V95G. We analyzed aggregation and membrane binding of all 8 mutants combining these three mutations. While G68E is particularly important in reducing the fibrillation and possible toxicity, the greatest effect is seen when all three mutations are present. Thus a small number of mutations can significantly reduce aSN toxicity.

AB - The intrinsically disordered protein α-synuclein (aSN) forms insoluble aggregates in the brains of Parkinson's Disease patients. Cytotoxicity is attributed to a soluble aSN oligomeric species which permeabilizes membranes significantly more than monomers and fibrils. In humans, the mutation A53T induces early-onset PD and increases aSN oligomerization and fibrillation propensity, but Thr53 occurs naturally in aSN of most animals. We compared aSN from elephant, bowhead whale and pig with human aSN. While all three animal aSN showed significantly reduced fibrillation behavior, elephant aSN formed much more oligomer, and pig aSN much less, than human aSN. However, all animal aSN oligomers showed decreased permeabilization towards anionic lipid vesicles, indicative of lowered cytotoxicity. These animal aSN share three substitutions compared to human aSN: A53T, G68E and V95G. We analyzed aggregation and membrane binding of all 8 mutants combining these three mutations. While G68E is particularly important in reducing the fibrillation and possible toxicity, the greatest effect is seen when all three mutations are present. Thus a small number of mutations can significantly reduce aSN toxicity.

UR - http://www.scopus.com/inward/record.url?scp=85052324168&partnerID=8YFLogxK

U2 - 10.1021/acs.biochem.8b00627

DO - 10.1021/acs.biochem.8b00627

M3 - Journal article

C2 - 30067901

VL - 57

SP - 5145

EP - 5158

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 34

ER -