Two conformationally distinct α-synuclein oligomers share common epitopes and the ability to impair long-term potentiation

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Two conformationally distinct α-synuclein oligomers share common epitopes and the ability to impair long-term potentiation. / van Diggelen, Femke; Hrle, Dean; Apetri, Mihaela; Christiansen, Gunna; Rammes, Gerhard; Tepper, Armand; Otzen, Daniel Erik.

I: PLOS ONE, Bind 14, Nr. 3, 0213663, 03.2019.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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van Diggelen, Femke ; Hrle, Dean ; Apetri, Mihaela ; Christiansen, Gunna ; Rammes, Gerhard ; Tepper, Armand ; Otzen, Daniel Erik. / Two conformationally distinct α-synuclein oligomers share common epitopes and the ability to impair long-term potentiation. I: PLOS ONE. 2019 ; Bind 14, Nr. 3.

Bibtex

@article{356acfa3e24e4e439c831b68679bf711,
title = "Two conformationally distinct α-synuclein oligomers share common epitopes and the ability to impair long-term potentiation",
abstract = "Parkinson's Disease (PD) is a neurodegenerative disease for which there currently is no cure. Aggregation of the pre-synaptic protein α-synuclein (aSN) into oligomers (αSOs) is believed to play a key role in PD pathology, but little is known about αSO formation in vivo and how they induce neurodegeneration. Both the naturally occurring polyunsaturated fatty acid docosahexaenoic acid (DHA) and the lipid peroxidation product 4-hydroxynonenal (HNE), strongly upregulated during ROS conditions, stimulate the formation of αSOs, highlighting a potential role in PD. Yet, insight into αSOs structure and biological effects is still limited as most oligomer preparations studied to date are heterogeneous in composition. Here we have aggregated aSN in the presence of HNE and DHA and purified the αSOs using size exclusion chromatography. Both compounds stimulate formation of spherical αSOs containing anti-parallel β-sheet structure which have the same shape as unmodified αSOs though ca. 2-fold larger. Furthermore, the yield and stabilities of these oligomers are significantly higher than for unmodified aSN. Both modified and unmodified αSOs permeabilize synthetic vesicles, show high co-localisation with glutamatergic synapses and decrease Long Term Potentiation (LTP), in line with the reported synaptotoxic effects of αSOs. We conclude that DHA- and HNE-αSOs are convenient models for pathogenic disease-associated αSOs in PD.",
keywords = "AMYLOID OLIGOMERS, ANTIPARALLEL BETA-SHEET, FATTY-ACIDS, LEWY BODY, MECHANISM, NEURONS, OXIDATIVE STRESS, SECONDARY STRUCTURE, SYNAPTIC DYSFUNCTION, TRANSMISSION",
author = "{van Diggelen}, Femke and Dean Hrle and Mihaela Apetri and Gunna Christiansen and Gerhard Rammes and Armand Tepper and Otzen, {Daniel Erik}",
year = "2019",
month = mar,
doi = "10.1371/journal.pone.0213663",
language = "English",
volume = "14",
journal = "P L o S One",
issn = "1932-6203",
publisher = "public library of science",
number = "3",

}

RIS

TY - JOUR

T1 - Two conformationally distinct α-synuclein oligomers share common epitopes and the ability to impair long-term potentiation

AU - van Diggelen, Femke

AU - Hrle, Dean

AU - Apetri, Mihaela

AU - Christiansen, Gunna

AU - Rammes, Gerhard

AU - Tepper, Armand

AU - Otzen, Daniel Erik

PY - 2019/3

Y1 - 2019/3

N2 - Parkinson's Disease (PD) is a neurodegenerative disease for which there currently is no cure. Aggregation of the pre-synaptic protein α-synuclein (aSN) into oligomers (αSOs) is believed to play a key role in PD pathology, but little is known about αSO formation in vivo and how they induce neurodegeneration. Both the naturally occurring polyunsaturated fatty acid docosahexaenoic acid (DHA) and the lipid peroxidation product 4-hydroxynonenal (HNE), strongly upregulated during ROS conditions, stimulate the formation of αSOs, highlighting a potential role in PD. Yet, insight into αSOs structure and biological effects is still limited as most oligomer preparations studied to date are heterogeneous in composition. Here we have aggregated aSN in the presence of HNE and DHA and purified the αSOs using size exclusion chromatography. Both compounds stimulate formation of spherical αSOs containing anti-parallel β-sheet structure which have the same shape as unmodified αSOs though ca. 2-fold larger. Furthermore, the yield and stabilities of these oligomers are significantly higher than for unmodified aSN. Both modified and unmodified αSOs permeabilize synthetic vesicles, show high co-localisation with glutamatergic synapses and decrease Long Term Potentiation (LTP), in line with the reported synaptotoxic effects of αSOs. We conclude that DHA- and HNE-αSOs are convenient models for pathogenic disease-associated αSOs in PD.

AB - Parkinson's Disease (PD) is a neurodegenerative disease for which there currently is no cure. Aggregation of the pre-synaptic protein α-synuclein (aSN) into oligomers (αSOs) is believed to play a key role in PD pathology, but little is known about αSO formation in vivo and how they induce neurodegeneration. Both the naturally occurring polyunsaturated fatty acid docosahexaenoic acid (DHA) and the lipid peroxidation product 4-hydroxynonenal (HNE), strongly upregulated during ROS conditions, stimulate the formation of αSOs, highlighting a potential role in PD. Yet, insight into αSOs structure and biological effects is still limited as most oligomer preparations studied to date are heterogeneous in composition. Here we have aggregated aSN in the presence of HNE and DHA and purified the αSOs using size exclusion chromatography. Both compounds stimulate formation of spherical αSOs containing anti-parallel β-sheet structure which have the same shape as unmodified αSOs though ca. 2-fold larger. Furthermore, the yield and stabilities of these oligomers are significantly higher than for unmodified aSN. Both modified and unmodified αSOs permeabilize synthetic vesicles, show high co-localisation with glutamatergic synapses and decrease Long Term Potentiation (LTP), in line with the reported synaptotoxic effects of αSOs. We conclude that DHA- and HNE-αSOs are convenient models for pathogenic disease-associated αSOs in PD.

KW - AMYLOID OLIGOMERS

KW - ANTIPARALLEL BETA-SHEET

KW - FATTY-ACIDS

KW - LEWY BODY

KW - MECHANISM

KW - NEURONS

KW - OXIDATIVE STRESS

KW - SECONDARY STRUCTURE

KW - SYNAPTIC DYSFUNCTION

KW - TRANSMISSION

UR - http://www.scopus.com/inward/record.url?scp=85063322937&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0213663

DO - 10.1371/journal.pone.0213663

M3 - Journal article

C2 - 30901378

VL - 14

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 3

M1 - 0213663

ER -