Universität zu Köln

Mackmull, Marie-Therese ORCID: 0000-0003-2928-1144, Nagel, Luise ORCID: 0000-0001-8844-7234, Sesterhenn, Fabian, Muntel, Jan ORCID: 0000-0003-2320-5829, Grossbach, Jan ORCID: 0000-0002-9394-5665, Stalder, Patrick, Bruderer, Roland, Reiter, Lukas, van de Berg, Wilma D. J., de Souza, Natalie, Beyer, Andreas and Picotti, Paola (2022). Global, in situ analysis of the structural proteome in individuals with Parkinson's disease to identify a new class of biomarker. Nat. Struct. Mol. Biol., 29 (10). S. 978 - 1004. BERLIN: NATURE PORTFOLIO. ISSN 1545-9985

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Abstract

Parkinson's disease (PD) is a prevalent neurodegenerative disease for which robust biomarkers are needed. Because protein structure reflects function, we tested whether global, in situ analysis of protein structural changes provides insight into PD pathophysiology and could inform a new concept of structural disease biomarkers. Using limited proteolysis-mass spectrometry (LiP-MS), we identified 76 structurally altered proteins in cerebrospinal fluid (CSF) of individuals with PD relative to healthy donors. These proteins were enriched in processes misregulated in PD, and some proteins also showed structural changes in PD brain samples. CSF protein structural information outperformed abundance information in discriminating between healthy participants and those with PD and improved the discriminatory performance of CSF measures of the hallmark PD protein alpha-synuclein. We also present the first analysis of inter-individual variability of a structural proteome in healthy individuals, identifying biophysical features of variable protein regions. Although independent validation is needed, our data suggest that global analyses of the human structural proteome will guide the development of novel structural biomarkers of disease and enable hypothesis generation about underlying disease processes.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mackmull, Marie-Therese UNSPECIFIED orcid.org/0000-0003-2928-1144 UNSPECIFIED Nagel, Luise UNSPECIFIED orcid.org/0000-0001-8844-7234 UNSPECIFIED Sesterhenn, Fabian UNSPECIFIED UNSPECIFIED UNSPECIFIED Muntel, Jan UNSPECIFIED orcid.org/0000-0003-2320-5829 UNSPECIFIED Grossbach, Jan UNSPECIFIED orcid.org/0000-0002-9394-5665 UNSPECIFIED Stalder, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruderer, Roland UNSPECIFIED UNSPECIFIED UNSPECIFIED Reiter, Lukas UNSPECIFIED UNSPECIFIED UNSPECIFIED van de Berg, Wilma D. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Souza, Natalie UNSPECIFIED UNSPECIFIED UNSPECIFIED Beyer, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Picotti, Paola UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-685378
DOI:	10.1038/s41594-022-00837-0
Journal or Publication Title:	Nat. Struct. Mol. Biol.
Volume:	29
Number:	10
Page Range:	S. 978 - 1004
Date:	2022
Publisher:	NATURE PORTFOLIO
Place of Publication:	BERLIN
ISSN:	1545-9985
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DATA-INDEPENDENT ACQUISITION; CEREBROSPINAL-FLUID; ALPHA-SYNUCLEIN; ALZHEIMERS-DISEASE; NEUROPATHOLOGIC ASSESSMENT; R PACKAGE; MECHANISMS; STANDARDIZATION; METAANALYSIS; ASSOCIATION Multiple languages Biochemistry & Molecular Biology; Biophysics; Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68537