Global, in Situ Analysis of the Structural Proteome in Individuals with Parkinson's Disease to Identify a New Class of Biomarker

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2022 Oct 12

PMID 36224378

Authors

Marie-Therese Mackmull

Luise Nagel

Fabian Sesterhenn

Jan Muntel

Jan Grossbach

Patrick Stalder

Roland Bruderer

Lukas Reiter

Wilma D J van de Berg

Natalie de Souza

Andreas Beyer

Paola Picotti

Affiliations

Soon will be listed here.

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 α-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.

Citing Articles

Post-translational modifications orchestrate the intrinsic signaling bias of GPR52.

Zhang B, Ge W, Ma M, Li S, Yu J, Yang G Nat Chem Biol. 2025; .

PMID: 40087539 DOI: 10.1038/s41589-025-01864-w.

π-HuB: the proteomic navigator of the human body.

He F, Aebersold R, Baker M, Bian X, Bo X, Chan D Nature. 2024; 636(8042):322-331.

PMID: 39663494 DOI: 10.1038/s41586-024-08280-5.

Global analysis of endogenous protein disorder in cells.

Zhang S, Owyong T, Sanislav O, Englmaier L, Sui X, Wang G Nat Methods. 2024; 22(1):124-134.

PMID: 39587358 DOI: 10.1038/s41592-024-02507-z.

DescribePROT Database of Residue-Level Protein Structure and Function Annotations.

Zhao B, Basu S, Kurgan L Methods Mol Biol. 2024; 2867:169-184.

PMID: 39576581 DOI: 10.1007/978-1-0716-4196-5_10.

Using in vivo intact structure for system-wide quantitative analysis of changes in proteins.

Son A, Kim H, Diedrich J, Bamberger C, McClatchy D, Lipton S Nat Commun. 2024; 15(1):9310.

PMID: 39468068 PMC: 11519357. DOI: 10.1038/s41467-024-53582-x.

References

Kennedy B, Berger S, Brunet A, Campisi J, Cuervo A, Epel E . Geroscience: linking aging to chronic disease. Cell. 2014; 159(4):709-13. PMC: 4852871. DOI: 10.1016/j.cell.2014.10.039. View

Cilento E, Jin L, Stewart T, Shi M, Sheng L, Zhang J . Mass spectrometry: A platform for biomarker discovery and validation for Alzheimer's and Parkinson's diseases. J Neurochem. 2018; 151(4):397-416. PMC: 6535381. DOI: 10.1111/jnc.14635. View

Jiang R, Rong C, Ke R, Meng S, Yan X, Ke H . Differential proteomic analysis of serum exosomes reveals alterations in progression of Parkinson disease. Medicine (Baltimore). 2019; 98(41):e17478. PMC: 6799836. DOI: 10.1097/MD.0000000000017478. View

Tzeng S, Kalodimos C . Protein activity regulation by conformational entropy. Nature. 2012; 488(7410):236-40. DOI: 10.1038/nature11271. View

Henzler-Wildman K, Kern D . Dynamic personalities of proteins. Nature. 2007; 450(7172):964-72. DOI: 10.1038/nature06522. View

Schopper S, Kahraman A, Leuenberger P, Feng Y, Piazza I, Muller O . Measuring protein structural changes on a proteome-wide scale using limited proteolysis-coupled mass spectrometry. Nat Protoc. 2017; 12(11):2391-2410. DOI: 10.1038/nprot.2017.100. View

Cappelletti V, Hauser T, Piazza I, Pepelnjak M, Malinovska L, Fuhrer T . Dynamic 3D proteomes reveal protein functional alterations at high resolution in situ. Cell. 2020; 184(2):545-559.e22. PMC: 7836100. DOI: 10.1016/j.cell.2020.12.021. View

Spillantini M, Schmidt M, Lee V, Trojanowski J, Jakes R, Goedert M . Alpha-synuclein in Lewy bodies. Nature. 1997; 388(6645):839-40. DOI: 10.1038/42166. View

Braak H, Del Tredici K, Rub U, de Vos R, Jansen Steur E, Braak E . Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2002; 24(2):197-211. DOI: 10.1016/s0197-4580(02)00065-9. View

10.

Maass F, Schulz I, Lingor P, Mollenhauer B, Bahr M . Cerebrospinal fluid biomarker for Parkinson's disease: An overview. Mol Cell Neurosci. 2018; 97:60-66. DOI: 10.1016/j.mcn.2018.12.005. View

11.

Borrageiro G, Haylett W, Seedat S, Kuivaniemi H, Bardien S . A review of genome-wide transcriptomics studies in Parkinson's disease. Eur J Neurosci. 2017; 47(1):1-16. DOI: 10.1111/ejn.13760. View

12.

Majbour N, Vaikath N, van Dijk K, Ardah M, Varghese S, Vesterager L . Oligomeric and phosphorylated alpha-synuclein as potential CSF biomarkers for Parkinson's disease. Mol Neurodegener. 2016; 11:7. PMC: 4717559. DOI: 10.1186/s13024-016-0072-9. View

13.

Parnetti L, Gaetani L, Eusebi P, Paciotti S, Hansson O, El-Agnaf O . CSF and blood biomarkers for Parkinson's disease. Lancet Neurol. 2019; 18(6):573-586. DOI: 10.1016/S1474-4422(19)30024-9. View

14.

van Dijk K, Persichetti E, Chiasserini D, Eusebi P, Beccari T, Calabresi P . Changes in endolysosomal enzyme activities in cerebrospinal fluid of patients with Parkinson's disease. Mov Disord. 2013; 28(6):747-54. DOI: 10.1002/mds.25495. View

15.

van Steenoven I, Majbour N, Vaikath N, Berendse H, van der Flier W, van de Berg W . α-Synuclein species as potential cerebrospinal fluid biomarkers for dementia with lewy bodies. Mov Disord. 2018; 33(11):1724-1733. PMC: 6519232. DOI: 10.1002/mds.111. View

16.

van Dijk K, Bidinosti M, Weiss A, Raijmakers P, Berendse H, van de Berg W . Reduced α-synuclein levels in cerebrospinal fluid in Parkinson's disease are unrelated to clinical and imaging measures of disease severity. Eur J Neurol. 2013; 21(3):388-94. DOI: 10.1111/ene.12176. View

17.

El-Agnaf O, Salem S, Paleologou K, Curran M, Gibson M, Court J . Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J. 2006; 20(3):419-25. DOI: 10.1096/fj.03-1449com. View

18.

Macron C, Lane L, Nunez Galindo A, Dayon L . Deep Dive on the Proteome of Human Cerebrospinal Fluid: A Valuable Data Resource for Biomarker Discovery and Missing Protein Identification. J Proteome Res. 2018; 17(12):4113-4126. DOI: 10.1021/acs.jproteome.8b00300. View

19.

Macron C, Lavigne R, Nunez Galindo A, Affolter M, Pineau C, Dayon L . Exploration of human cerebrospinal fluid: A large proteome dataset revealed by trapped ion mobility time-of-flight mass spectrometry. Data Brief. 2020; 31:105704. PMC: 7251648. DOI: 10.1016/j.dib.2020.105704. View

20.

Zhang J, Kurgan L . SCRIBER: accurate and partner type-specific prediction of protein-binding residues from proteins sequences. Bioinformatics. 2019; 35(14):i343-i353. PMC: 6612887. DOI: 10.1093/bioinformatics/btz324. View