Project Title: Characterising regiospecific lipid phenotypes in human PD and Gaucher tissues using next-generation MSI and IMS

Principal Investigators: Kim Ekroos (Lipidomics Consulting, Ltd), Shane Ellis (University of
Wollongong), Nico Verbeeck (Aspect Analytics NV)

Study Rationale:
The contribution of glycosphingolipids to Parkinson’s disease (PD) is not fully understood. However, it is known that mutations in the GBA1 gene, encoding for glucocerebrocidase (GCase), is the most prevalent risk factor for PD. The resulting deficit in GCase activity leads to accumulation of the natural cellular fats; glucosylceramide and glucosylsphingosine. Our research interest is understanding the mechanistic and metabolic details of these complex essential fats and their upstream and downstream metabolic products, collectively referred as glycosphingolipids. However, the structural heterogeneity, local concentrations, and distributions of the glycosphingolipids within PD brain regions are not well understood.

Hypothesis:
Our hypothesis is that alterations in the metabolism of selective glycosphingolipids in specific brain regions contributes to early PD onset and accelerated progression rates.

Study Design:
Glycosphingolipids are a rich family of essential molecules in brain fulfilling multiple functional roles from cell structure and transport to signaling. However, understanding the role of glycosphingolipids in PD is difficult due to their high structural complexity, and unclear localizations and concentrations within brain regions. Here, we utilize a high-resolving, two-dimensional approach to measure precise content and localization of brain glycosphingolipids in PD and Gaucher disease (GD) patient tissues. We will determine whether certain glycosphingolipids stand out in specific brain regions in diseased tissues and will conduct deep learning computational approaches to better understand how these region-selective glycosphingolipid levels can be restored to a healthy state. In this way, we intend to get a more complete picture of the how alterations in glycosphingolipids contribute to PD and in what ways we can restore lipid imbalances for PD therapies.

Impact on Diagnosis/Treatment of Parkinson’s disease:
Results in support of our hypothesis will shed new light on the role of glycosphingolipid metabolism and brain localization in PD pathology. Understanding aberrant glycosphingolipid in specific brain regions in PD patients will lay the foundation for future studies identifying new biomarkers and therapeutic avenues for the treatment of PD.

Next Steps for Development:
Characterising new potential targets and biomarkers could be undertaken to identify more selective targets and diagnostic measurements for PD. By identifying a more translatable preclinical PD model, this may open up new strategies to accelerate the therapeutics of PD.