University of Cambridge

Alumnus, Chemical Engineering and Biotechnology

DOC Fellow of the Austrian Academy of Science

Downing

Thesis Title: Proteomics and Glycomics Biomarker Discovery for Neuropsychiatric Disorders

About

Schizophrenia is a major neuropsychiatric disorder that currently affects 1% of the population. There is no biochemical diagnostic test available, meaning that patients must undergo lengthy evaluation periods before an accurate diagnosis can be given.  Body fluids such as blood and cerebrospinal fluid (CSF) represent ideal candidates for the identification of potential biomarkers for this disease.

In the search for better diagnostics for schizophrenia I have investigated the sub-proteome of glycosylated proteins. I used glycan post translational modifications to investigate changes in the protein and glycan part of glycoproteins. I have developed new strategies for glyco-protein analyses by combining affinity chromatography with mass spectrometry platforms. The combination of these proteomics methods yielded serum protein markers for schizophrenia such as alpha-defensins and the masses of several unidentified proteins. In this thesis, I report comprehensive high-throughput N-glycan analyses from serum and cerebrospinal fluid glycomes of patients and controls. This is the first report of N-glycan structures from cerebrospinal fluid and low abundant serum proteins. I have investigated these N-glycan pools in first onset, unmedicated schizophrenia patients and identified several N-glycans in serum and CSF which distinguish schizophrenia patients from health individuals.  For example the tetra-antennary glycan A4G4LacS4 showed a two fold increase in serum of male schizophrenia patients. Glycan changes in the CSF showed a general down regulation in schizophrenia patients and a high predictive power for distinguishing patients from controls. These changes might be associated with the down-regulation of glycosyltransferases in the prefrontal cortex from schizophrenia patients.

The findings from this thesis suggest that a dysfunction in protein glycosylation is important to disease pathology in schizophrenia. These could be used for early diagnosis and treatment monitoring. Furthermore, these findings might initiate new treatment approaches that target glycosyltransferases for the development of better neuropsychiatric treatment.

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