title: Aggregation-induced changes in the chemical exchange saturation transfer (CEST) signals of proteins.
abstract: Chemical exchange saturation transfer (CEST) is an MRI technique that allows mapping of biomolecules (small metabolites, proteins) with nearly the sensitivity of conventional water proton MRI. In living organisms, several tissue-specific CEST effects have been observed and successfully applied to diagnostic imaging. In these studies, particularly the signals of proteins showed a distinct correlation with pathological changes. However, as CEST effects depend on various properties that determine and affect the chemical exchange processes, the origins of the observed signal changes remain to be understood. In this study, protein aggregation was identified as an additional process that is encoded in the CEST signals of proteins. Investigation of distinct proteins that are involved in pathological disorders, namely amyloid beta and huntingtin, revealed a significant decrease of all protein CEST signals upon controlled aggregation. This finding is of particular interest with regard to diagnostic imaging of patients with neurodegenerative diseases that involve amyloidogenesis, such as Alzheimer's or Huntington's disease. To investigate whether the observed CEST signal decrease also occurs in heterogeneous mixtures of aggregated cellular proteins, and thus prospectively in tissue, heat-shocked yeast cell lysates were employed. Additionally, investigation of different cell compartments verified the assignment of the protein CEST signals to the soluble part of the proteome. The results of in vitro experiments demonstrate that aggregation affects the CEST signals of proteins. This observation can enable hypotheses for CEST imaging as a non-invasive diagnostic tool for monitoring pathological alterations of the proteome in vivo.
authors.affiliation: Division of Medical Physics in Radiology, Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Goerke
authors.affiliation: Division of Medical Physics in Radiology, Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Katharina S
authors.initials: KS
authors.lastname: Milde
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Robert-Rössle-Straße 10, 13092, Berlin, Germany.
authors.forename: Raul
authors.initials: R
authors.lastname: Bukowiecki
authors.affiliation: Division of Functional Genome Analysis, Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Kunz
authors.affiliation: Molecular Structure Analysis, Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Karel D
authors.initials: KD
authors.lastname: Klika
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Robert-Rössle-Straße 10, 13092, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wiglenda
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Mogk
authors.affiliation: Max Delbrück Center for Molecular Medicine (MDC), Proteomics and Molecular Mechanisms of Neurodegenerative Diseases, Robert-Rössle-Straße 10, 13092, Berlin, Germany.
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
authors.affiliation: Zentrum für Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Allianz, Im Neuenheimer Feld 282, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bukau
authors.affiliation: Division of Medical Physics in Radiology, Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Ladd
authors.affiliation: Division of Medical Physics in Radiology, Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bachert
authors.affiliation: Division of Medical Physics in Radiology, Deutsches Krebsforschungszentrum [German Cancer Research Center] (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Baden-Württemberg, Germany.|Max Planck Institute for Biological Cybernetics, Department of High-Field Magnetic Resonance, Spemannstraße 41, 72076, Tübingen, Baden-Württemberg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Zaiss
mesh_terms: D002458:Cell Fractionation; D045424:Complex Mixtures / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000737:chemistry*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D057054:Molecular Imaging / Q000379:methods*; D066329:Protein Aggregates; D011506:Proteins / Q000737:chemistry*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D015003:Yeasts / Q000737:chemistry*
chemical_list: D045424:Complex Mixtures; D006360:Heat-Shock Proteins; D066329:Protein Aggregates; D011506:Proteins
keywords: CEST; amide protons; amyloidogenesis; protein aggregation; rNOE; yeast cell lysate