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Nitroalkylation of α-Synuclein by Nitro-Oleic Acid: Implications for Parkinson’s Disease

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Bioactive Lipids in Health and Disease

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1127))

Abstract

α-Synuclein (α-syn) represents the main component of the amyloid aggregates present in Parkinson’s disease and other neurodegenerative disorders, collectively named synucleinopathies. Although α-syn is considered a natively unfolded protein, it shows great structural flexibility which allows the protein to adopt highly rich beta-sheet structures like protofibrils, oligomers and fibrils. In addition, this protein can adopt alpha-helix rich structures when interacts with fatty acids or acidic phospholipid vesicle membranes. When analyzing the toxicity of α-syn, protein oligomers are thought to be the main neurotoxic species by mechanisms that involve modification of intracellular calcium levels, mitochondrial and lysosomal function. Extracellular fibrillar α-syn promotes intracellular protein aggregation and shows many toxic effects as well. Nitro-fatty acids (nitroalkenes) represent novel pleiotropic anti-inflammatory signaling mediators that could interact with α-syn to exert unraveling actions. Herein, we demonstrated that nitro-oleic acid (NO2-OA) nitroalkylate α-syn, forming a covalent adduct at histidine-50. The nitroalkylated-α-syn exhibited strong affinity for phospholipid vesicles, moving the protein to the membrane compartment independent of composition of the membrane phospholipids. Moreover, NO2-OA-modified α-syn showed a reduced capacity to induce α-syn fibrillization compared to the non-nitrated oleic acid. From this data we hypothesize that nitroalkenes, in particular NO2-OA, may inhibit α-syn fibril formation exerting protective actions in Parkinson’s disease.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic Lateral Sclerosis

ARE:

antioxidant responsive elements

FABP:

fatty acid binding protein

GAPDH:

glyceraldehyde 3-phosphate dehydro-genase

4-HNE:

4-hydroxynonenal

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MSA:

multiple system atrophy

NO2-OA:

nitro-oleic acid

NSAID:

nonsteroidal anti-inflammatory drugs

OA:

oleic acid

PD:

Parkinson’s disease

PSD:

post source decay

RNS:

reactive nitrogen species

ROS:

reactive oxygen species

SDS:

sodium dodecyl sulfate

SNARE:

soluble NSF attachment receptor

α-syn:

alpha-synuclein

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Acknowledgment

We thank Bruce A. Freeman (University of Pittsburgh, Pittsburgh, PA, United States) for provide us with NO2-OA and Carlos Batthyány from the Institut Pasteur de Montevideo for technical assistance. This work was supported by Agencia Nacional de Investigación e Innovación (ANII), Uruguay (ANII-FCE 2011_1_6260 to J.M.S.) and fellowships from ANII, Comisión Sectorial de Investigación Científica and Programa de Desarrollo de las Ciencias Básicas (PEDECIBA) to C.C.

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Authors and Affiliations

  1. Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Cecilia Chavarría, Andrés Trostchansky, Homero Rubbo & José M. Souza

  2. Institut Pasteur de Montevideo, Instituto de Investigaciones Biológicas Clemente Estable, Unidad de Bioquímica y Proteómica Analíticas, Montevideo, Uruguay

    Rosario Durán

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  1. Cecilia Chavarría
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  2. Andrés Trostchansky
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  3. Rosario Durán
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  4. Homero Rubbo
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  5. José M. Souza
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Correspondence to José M. Souza .

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Editors and Affiliations

  1. Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Andres Trostchansky

  2. Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    Homero Rubbo

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Chavarría, C., Trostchansky, A., Durán, R., Rubbo, H., Souza, J.M. (2019). Nitroalkylation of α-Synuclein by Nitro-Oleic Acid: Implications for Parkinson’s Disease. In: Trostchansky, A., Rubbo, H. (eds) Bioactive Lipids in Health and Disease. Advances in Experimental Medicine and Biology, vol 1127. Springer, Cham. https://doi.org/10.1007/978-3-030-11488-6_11

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