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Mass Spectrometric Analysis of Lewy Body-Enriched α-Synuclein in Parkinson's Disease

Journal article
Authors Payel Bhattacharjee
Annika Öhrfelt
T. Lashley
Kaj Blennow
Ann Brinkmalm
Henrik Zetterberg
Published in Journal of Proteome Research
Volume 18
Issue 5
Pages 2109-2120
ISSN 1535-3893
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Pages 2109-2120
Language - English
Links doi.org/10.1021/acs.jproteome.8b009...
Subject categories Neurosciences

Abstract

- Parkinson's disease (PD) is characterized by intraneuronal inclusions of aggregated α-synuclein protein (so-called Lewy bodies) in distinct brain regions. Multiple posttranslational modifications may affect the structure and function of α-synuclein. Mass spectrometry-based analysis may be useful for the characterization and quantitation of α-synuclein forms, but has proven challenging, mainly due to the insolubility of Lewy bodies in aqueous buffer. In the present study, we developed a novel method by combining differential solubilization with immunoprecipitation and targeted proteomics using liquid chromatography and tandem mass spectrometry. Brain tissue homogenization and sample preparation were modified to facilitate analysis of soluble, detergent-soluble, and detergent-insoluble protein fractions (Lewy body-enriched). The method was used to compare α-synuclein forms from cingulate cortex (affected) and occipital cortex (unaffected) in two study sets of PD patients and controls. We identified 20 modified α-synuclein variants, including species with N-terminal acetylation and C-terminal truncations at amino acids 103 and 119. The levels of α-synuclein forms Ac-α-syn 1-6 , α-syn 13-21 , α-syn 35-43 , α-syn 46-58 , α-syn 61-80 , and α-syn 81-96 except α-syn 103-119 were significantly increased in PD cingulate region compared to controls in the Lewy body-enriched α-synuclein fraction. In the soluble fraction, only Ac-α-syn 1-6 was significantly increased in PD compared to controls. None of the detected α-synuclein variants were Lewy body-specific, but acetylated forms should be examined further as potential biomarkers for abnormal α-synuclein accumulation. © Copyright 2019 American Chemical Society.

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