Date of Award

2015

Degree Type

Thesis

Degree Name

Master of Science (Human Biology)

School

School of Medical Sciences

Faculty

Faculty of Health, Engineering and Science

First Advisor

Professor Wei Wang

Second Advisor

Dr Meghan Thomas

Abstract

For neurodegenerative diseases, interventions during the early stages of the disease, before significant neurodegeneration has occurred, are associated with an increased probability of slowing or halting the disease process. In order to intervene early, it is essential that an accurate diagnosis is obtained and that disease progression can be monitored. This is particularly relevant for Parkinson’s disease (PD; International Classification of Diseases version 10) because significant neurodegeneration has already occurred by the time the clinical motor symptoms are present. Therefore, the development of translatable, high-throughput biomarkers for large scale population screening is a crucial area of research. Of promise are the emerging “omics” technologies, which enable the detection of preclinical biomolecule fluctuations associated with the development of different diseases.

One such field is glycomics which is the study of the set of sugar structures, hereon in known as glycans, in a given protein, cell or tissue. Notably, the functional diversity of proteins is increased by several magnitudes with the addition of glycans, a process known as glycosylation. The glycosylation of certain proteins, including immunoglobulin G (IgG), has been found to remain fairly stable over short periods of time, with modifications thought to result from changes in the cellular environment or disease presence. Indeed, IgG has the ability to exert both anti-inflammatory and pro-inflammatory effects throughout the body and these properties are controlled by the N-glycosylation of the fragment crystallisable (Fc) portion.

To our knowledge, this was the first time that the potential of using IgG glycomic biomarkers to identify people with PD, as well as identify people with PD who are at risk of cognitive decline, was investigated. It was demonstrated that the peripheral IgG glycome in the PD cases was indicative of an increased capacity to biologically age. While advancing age has previously been associated with modifications to the glycosylation of IgG, making them more pro-inflammatory, advancing age was only associated with significant increases in modifications to the peripheral IgG glycome that infer more pro-inflammatory IgG in the PD cases but not the controls. In PD, the severity of the underlying pathology increases as the individual ages and, therefore, is a confounder of the effect of advancing age on pro-inflammation. Consequently, the peripheral IgG in people with PD have a propensity to become more pro-inflammatory at a faster rate as they age, and this may be linked to the severity of pathology during the course of the disease. PD has a heterogeneous presentation of clinical symptoms, and many factors contribute to the development of the disease. While this is true, it was demonstrated that the peripheral IgG glycome does not have utility in identifying risk of cognitive decline, which would result from progression of PD pathology in the central nervous system (CNS). These results are indicative of the peripheral IgG interacting with PD pathology in the enteric nervous system (ENS) as well as when it propagates from the ENS to the CNS along the vagal nerve. Inflammation may facilitate the neuron-to-neuron propagation of PD inclusions along this pathway and thus be a contributor to PD development during the prodromal phase. Hence, the peripheral IgG glycome may be useful as a novel biomarker of PD presence in the prodromal phase of the disease.

Share

 
COinS