Proteomics - Biomarkerforschung in der Psychiatrie

 

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Zusammenfassung

Durch die Genforschung („Genomics”) konnten in den letzten Jahrzehnten wichtige Erkenntnisse zu grundlegenden physiologischen und pathophysiologischen Prozessen gewonnen werden, die für die Psychiatrie relevant sind. Dadurch entstanden auch Hoffnungen für baldige klinische Anwendungsmöglichkeiten. Leider konnte die Genforschung jedoch bisher diesen hohen Erwartungen (z. B. im Hinblick auf diagnostische und therapeutische Optionen) nicht gerecht werden. Zunehmend wird klar, dass auch Prozesse wie alternatives Splicen der RNA und posttranslationale Modifikationen, die aus einem einzelnen Gen eine Vielzahl an Genprodukten entstehen lassen, beachtet werden müssen. Darüber hinaus spielen auch Signaltransduktionswege und Interaktionen von verschiedenen funktionellen Netzwerken im Gehirn eine wichtige Rolle, die nicht nur auf DNA- und RNA- sondern auch auf Protein-Ebene untersucht werden müssen. Dieser Notwendigkeit wird in der modernen Proteomforschung („Proteomics”) Rechnung getragen. Zur Anwendung kommen hier massenspektrometrische Methoden, um das Expressionsniveau von Proteinen, posttranslationale Modifikationen und Protein-Protein-Interaktionen zu erforschen. Durch solche proteomanalytischen Untersuchungen können in automatisierter Weise und unter einem hohen Durchsatz von Proben („high throughput”) Proteinmuster in postmortem-Gewebe, im Liquor oder Serum quantitativ und qualitativ bestimmt werden. So können wichtige neue Erkenntnisse auch zur Ätiopathogenese neuropsychiatrischer Erkrankungen gewonnen werden. Indem Proteinprofile von Patienten mit denen von gesunden Kontrollpersonen verglichen werden, ist es möglich, diagnostische und prognostische Biomarker zu identifizieren. Zusätzlich erleichtert die proteomanalytische Untersuchung von Medikamenteneffekten in vitro und in vivo die Entwicklung spezifischer und nebenwirkungsarmer Medikamente. In diesem Beitrag werden häufig verwendete proteomanalytische Techniken sowie Chancen und Limitationen dieser Methoden vorgestellt. Weiterhin werden die bisherigen Ergebnisse proteomanalytischer Studien zu klassischen neuropsychiatrischen Erkrankungen (Alzheimer-Demenz, Suchterkrankungen, Schizophrenie, Angsterkrankungen, Depression) zusammengefasst.

Abstract

Over the last decade, genomics research in psychiatry and neuroscience has provided important insights into genes expressed under different physiological and pathophysiological conditions. Contrary to the great expectations regarding a clinical use of these datasets, genomics failed to improve markedly the diagnostic and therapeutic options in brain disorders. Due to alternative splicing and posttranslational modifications, one single gene determines a multitude of gene products. Therefore, in order to understand molecular processes in neuropsychiatric disorders, it is necessary to unravel signal transduction pathways and complex interaction networks on the level of proteins, not only DNA and mRNA. Proteomics utilises high-throughput mass spectrometric protein identification that can reveal protein expression levels, posttranslational modifications and protein-protein interactions. Proteomic tools have the power to identify quantitative and qualitative protein patterns in postmortem brain tissue, cerebrospinal fluid (CSF) or serum, thus increasing the knowledge about etiology and pathomechanisms of brain diseases. Comparing protein profiles in healthy and disease states provides an opportunity to establish specific diagnostic and prognostic biomarkers. In addition, proteomic studies of the effects of medication - in vitro and in vivo - might help to design specific pharmaceutical agents with fewer side effects. In this overview, we present the most widely used proteomic techniques and illustrate the potential and limitations of this field of research. Furthermore, we provide insight into the contributions of proteomics to the study of psychiatric diseases such as Alzheimer's disease, drug addiction, schizophrenia and depression.

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Prof. Dr. med. Dr. phil. J. Thome

Psychiatry Unit, The School of Medicine

Grove Building (113)

Singleton Park

Swansea SA2 8PP

United Kingdom

Email: j.thome@swan.ac.uk