Global, in situ analysis of the structural proteome in individuals with Parkinson's disease to identify a new class of biomarker
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. Mehr anzeigen
Publikationsstatus
publishedExterne Links
Zeitschrift / Serie
Nature Structural & Molecular BiologyBand
Seiten / Artikelnummer
Verlag
NatureOrganisationseinheit
03927 - Picotti, Paola / Picotti, Paola
Förderung
866004 - Three-dimensional dynamic views of proteomes as a novel readout for physiolgical and pathological alterations (EC)
823839 - European Proteomics Infrastructure Consortium providing Access (EC)