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

Bhattacharjee, P; Öhrfelt, A; Lashley, T; Blennow, K; Brinkmalm, A; Zetterberg, H; (2019) Mass Spectrometric Analysis of Lewy Body-Enriched α-Synuclein in Parkinson's Disease. Journal of Proteome Research , 18 (5) pp. 2109-2120. 10.1021/acs.jproteome.8b00982. Green open access

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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-syn1–6, α-syn13–21, α-syn35–43, α-syn46–58, α-syn61–80, and α-syn81–96 except α-syn103–119 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-syn1–6 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.

Type: Article
Title: Mass Spectrometric Analysis of Lewy Body-Enriched α-Synuclein in Parkinson's Disease
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.jproteome.8b00982
Publisher version: https://doi.org/10.1021/acs.jproteome.8b00982
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Lewy bodies; mass spectrometry; parallel reaction monitoring; Parkinson’s disease; α-synuclein
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10072865
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