Funded Studies
Objective/Rationale:
The objective of this study is to explore the role of glycans (sugars attached to proteins) in the development and progression of Parkinson’s disease (PD). Glycans play a key role in many important cellular processes, including signaling pathways and immune response, but have not been widely studied due to technical limitations. This study will leverage pharmaceutical company Ezose’s novel, high-throughput technology, the GlycanMap® platform, to discover PD-associated glycan changes in brain samples from pre-clinical models.
Project Description:
This study will analyze glycans isolated from brain stems of two PD models compared to control models. A total of 54 samples will be collected at three different time points over a four-month period in which the PD models exhibit physiological changes associated with PD, including impaired mobility and reduction of dopaminergic neurons. Glycans will be released from their parent proteins and analyzed using the GlycanMap® assay, which couples a bead-based glycan purification with mass spectrometry and proprietary bioinformatics to determine the composition and concentration of each glycan in the sample. Glycan concentrations will then be compared between groups and time points to discover changes associated with development and progression of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Glycans are involved in cell signaling, neural cell death and immune response, all of which play a role in PD. Glycan changes have also been implicated in other neurological diseases, including multiple sclerosis, Alzheimer’s disease, ALS and PD-associated dementia. This study will examine glycan changes associated with the development and/or progression of PD and may provide the foundation for development of biomarkers for diagnosis and monitoring of disease as well as new insights into disease biology.
Anticipated Outcome:
Glycan changes that emerge from this exploratory study can enhance our understanding of the molecular events that lead to development and progression of disease and symptoms and can provide new biomarkers that could be used to guide development of new therapeutics and/or improve clinical management of PD. These findings could also lead to the identification of new PD drug targets.
Final Outcome
A total of 138 N-linked glycans were detected and quantified in pre-clinical model brain stem lysates. Thirty-six of these glycans showed significant changes over time in the brain stems of DJ-1 and/or Pink1 PD models as compared to wild type models. Only one glycan showed similar changes over time in the brain stems of both Pink1 and DJ1 PD models and Pink1 PD models exhibited more time-dependent changes than DJ-1 PD models.
A total of 29 glycans exhibited time-dependent changes in Pink1 PD models. These changes could be separated into two categories: 1) sustained changes, where the concentration of 18 glycans increased gradually over the 3 time points 2) changes at six months, where the concentration of 11 glycans spiked at 6 months but decreased again by 8 months. Furthermore, the glycans tended to cluster into structurally-related groups. DJ-1 PD models exhibited decreases in two structurally related glycans and increases in 4 additional glycans.
Overall, while the magnitudes of the glycan changes observed in this study were relatively small (generally less than 20%), the observation that changes tended to cluster into structurally-related groups suggest that the observed changes are not random. The small magnitude of these changes may be a reflection of the early stage of disease in these models and the fact that not all models develop symptoms of PD over this timeframe. While the results presented here suggest that glycan changes associated with Parkinson’s disease can be detected early in the development of disease, further work is needed to more thoroughly characterize these changes.