Formation of covalent di-tyrosine dimers in recombinant α-synuclein

A van Maarschalkerweerd; MN Pedersen; H Peterson; M Nilsson; TTT Nguyen; T Skamris; K Rand; V Vetri; AE Langkilde; B Vestergaard

doi:10.1080/21690707.2015.1071302

Formation of covalent di-tyrosine dimers in recombinant α-synuclein

A van Maarschalkerweerd, MN Pedersen, H Peterson, M Nilsson, TTT Nguyen, T Skamris, K Rand, V Vetri, AE Langkilde, B Vestergaard

Department of Drug Design and Pharmacology

9 Citations (Scopus)

Abstract

Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.

Original language	English
Journal	Intrinsically Disordered Proteins
Volume	3
Issue number	1
Pages (from-to)	1-12
Number of pages	12
ISSN	null
DOIs	https://doi.org/10.1080/21690707.2015.1071302
Publication status	Published - 19 Oct 2015

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10.1080/21690707.2015.1071302

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title = "Formation of covalent di-tyrosine dimers in recombinant α-synuclein",

abstract = "Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.",

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T1 - Formation of covalent di-tyrosine dimers in recombinant α-synuclein

AU - van Maarschalkerweerd, A

AU - Pedersen, MN

AU - Peterson, H

AU - Nilsson, M

AU - Nguyen, TTT

AU - Skamris, T

AU - Rand, K

AU - Vetri, V

AU - Langkilde, AE

AU - Vestergaard, B

N1 - doi: 10.1080/21690707.2015.1071302

PY - 2015/10/19

Y1 - 2015/10/19

N2 - Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.

AB - Parkinson's disease is associated with fibril deposition in the diseased brain. Misfolding events of the intrinsically disordered synaptic protein α-synuclein are suggested to lead to the formation of transient oligomeric and cytotoxic species. The etiology of Parkinson's disease is further associated with mitochondrial dysfunction and formation of reactive oxygen species. Oxidative stress causes chemical modification of native α-synuclein, plausibly further influencing misfolding events. Here, we present evidence for the spontaneous formation of covalent di-tyrosine α-synuclein dimers in standard recombinant protein preparations, induced without extrinsic oxidative or nitrative agents. The dimers exhibit no secondary structure but advanced SAXS studies reveal an increased structural definition, resulting in a more hydrophobic micro-environment than the highly disordered monomer. Accordingly, monomers and dimers follow distinct fibrillation pathways.

U2 - 10.1080/21690707.2015.1071302

DO - 10.1080/21690707.2015.1071302

M3 - Journal article

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Formation of covalent di-tyrosine dimers in recombinant α-synuclein

Abstract

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