α-Synucleins from Animal Species Show Low Fibrillation Propensities and Weak Oligomer Membrane Disruption

Cagla Sahin; Lars Kjær; Mette Solvang Christensen; Jannik Pedersen; Gunna Christiansen; Adriana Michelle Wolf Pérez; Ian Max Møller; Jan J. Enghild; Jan S. Pedersen; Knud Larsen; Daniel E. Otzen

doi:10.1021/acs.biochem.8b00627

α-Synucleins from Animal Species Show Low Fibrillation Propensities and Weak Oligomer Membrane Disruption

Cagla Sahin, Lars Kjær, Mette Solvang Christensen, Jannik Pedersen, Gunna Christiansen, Adriana Michelle Wolf Pérez, Ian Max Møller, Jan J. Enghild, Jan S. Pedersen, Knud Larsen, Daniel E. Otzen^*

^*Kontaktforfatter

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

14 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Biochemistry
Vol/bind	57
Udgave nummer	34
Sider (fra-til)	5145-5158
Antal sider	14
ISSN	0006-2960
DOI	https://doi.org/10.1021/acs.biochem.8b00627
Status	Udgivet - 28 aug. 2018
Udgivet eksternt	Ja

Bibliografisk note

Funding Information:
*E-mail: dao@inano.au.dk. ORCID Daniel E. Otzen: 0000-0002-2918-8989 Author Contributions C.S. and L.K. contributed equally to this work. L.K. and D.E.O. conceived and designed experiments. C.S., L.K., M.S.C., J.N.P., and K.L. performed experiments. G.C., A.-M.W.P., I.M.M., J.J.E., and J.S.P. analyzed data. L.K., C.S., and D.E.O. wrote the manuscript. Funding D.E.O. and L.K. are supported by the Danish Research Council | Natural Sciences (Grant 12-127028) and the Parkinson Society of Denmark. C.S. and I.M.M. are supported by the Danish Research Council | Technology and Production (Grant 19725). Notes The authors declare no competing financial interest.

Publisher Copyright:
© 2018 American Chemical Society.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

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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 Jannik Pedersen and Gunna Christiansen and P{\'e}rez, {Adriana Michelle Wolf} and M{\o}ller, {Ian Max} and Enghild, {Jan J.} and Pedersen, {Jan S.} and Knud Larsen and Otzen, {Daniel E.}",

note = "Funding Information: *E-mail: dao@inano.au.dk. ORCID Daniel E. Otzen: 0000-0002-2918-8989 Author Contributions C.S. and L.K. contributed equally to this work. L.K. and D.E.O. conceived and designed experiments. C.S., L.K., M.S.C., J.N.P., and K.L. performed experiments. G.C., A.-M.W.P., I.M.M., J.J.E., and J.S.P. analyzed data. L.K., C.S., and D.E.O. wrote the manuscript. Funding D.E.O. and L.K. are supported by the Danish Research Council | Natural Sciences (Grant 12-127028) and the Parkinson Society of Denmark. C.S. and I.M.M. are supported by the Danish Research Council | Technology and Production (Grant 19725). Notes The authors declare no competing financial interest. Publisher Copyright: {\textcopyright} 2018 American Chemical Society. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

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doi = "10.1021/acs.biochem.8b00627",

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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 - Pedersen, Jannik

AU - Christiansen, Gunna

AU - Pérez, Adriana Michelle Wolf

AU - Møller, Ian Max

AU - Enghild, Jan J.

AU - Pedersen, Jan S.

AU - Larsen, Knud

AU - Otzen, Daniel E.

N1 - Funding Information: *E-mail: dao@inano.au.dk. ORCID Daniel E. Otzen: 0000-0002-2918-8989 Author Contributions C.S. and L.K. contributed equally to this work. L.K. and D.E.O. conceived and designed experiments. C.S., L.K., M.S.C., J.N.P., and K.L. performed experiments. G.C., A.-M.W.P., I.M.M., J.J.E., and J.S.P. analyzed data. L.K., C.S., and D.E.O. wrote the manuscript. Funding D.E.O. and L.K. are supported by the Danish Research Council | Natural Sciences (Grant 12-127028) and the Parkinson Society of Denmark. C.S. and I.M.M. are supported by the Danish Research Council | Technology and Production (Grant 19725). Notes The authors declare no competing financial interest. Publisher Copyright: © 2018 American Chemical Society. Copyright: Copyright 2018 Elsevier B.V., All rights reserved.

PY - 2018/8/28

Y1 - 2018/8/28

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.

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U2 - 10.1021/acs.biochem.8b00627

DO - 10.1021/acs.biochem.8b00627

M3 - Journal article

C2 - 30067901

SN - 0006-2960

VL - 57

SP - 5145

EP - 5158

JO - Biochemistry

JF - Biochemistry

IS - 34

ER -

α-Synucleins from Animal Species Show Low Fibrillation Propensities and Weak Oligomer Membrane Disruption

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