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Mass Spectrometric Analysis of Lewy Body-Enriched alpha-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 en
Links dx.doi.org/10.1021/acs.jproteome.8b...
Keywords alpha-synuclein, Lewy bodies, mass spectrometry, Parkinson's disease, parallel reaction monitoring, cerebrospinal-fluid, identification, phosphorylation, pathogenesis, aggregation, alzheimers, oligomers, cleavage, beta, csf
Subject categories Neurosciences

Abstract

Parkinson's disease (PD) is characterized by intraneuronal inclusions of aggregated alpha-synuclein protein (so-called Lewy bodies) in distinct brain regions. Multiple posttranslational modifications may affect the structure and function of alpha-synuclein. Mass spectrometry-based analysis may be useful for the characterization and quantitation of alpha-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 alpha-synuclein forms from cingulate cortex (affected) and occipital cortex (unaffected) in two study sets of PD patients and controls. We identified similar to 20 modified alpha-synuclein variants, including species with N-terminal acetylation and C-terminal truncations at amino acids 103 and 119. The levels of alpha-synuclein forms Ac-alpha-syn(1-6), alpha-syn(13-21), alpha-syn(35-43), alpha-syn(46-58), alpha-syn(61-80), and alpha-syn(81-96) except alpha-syn(103-119) were significantly increased in PD cingulate region compared to controls in the Lewy body-enriched alpha-synuclein fraction. In the soluble fraction, only Ac-alpha-syn(1-6) was significantly increased in PD compared to controls. None of the detected alpha-synuclein variants were Lewy body-specific, but acetylated forms should be examined further as potential biomarkers for abnormal alpha-synuclein accumulation.

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