More Than Pretty Pictures: Ion Imaging of Lipid Content and Flux Kinetics in Models of Parkinson’s Disease

Study Rationale:

Glycosphingolipids are natural cellular fats. They are components of cellular membranes that fulfill multiple functional roles, from cell structure and transport to signaling. The contribution of glycosphingolipids to Parkinson’s disease is not fully understood. However, it is known that mutations in the GBA1 gene, encoding for the enzyme glucocerebrocidase (GCase), is the most prevalent risk factor for Parkinson’s. The resulting deficit in GCase activity leads to accumulation of two glycosphingolipids, glucosylceramide and glucosylsphingosine. Our research interest is understanding the mechanistic and metabolic details of these complex and essential fats, and their role within brain regions affected by Parkinson’s.

Hypothesis:

Our hypothesis is that alterations in the metabolism of selective glycosphingolipids in specific brain regions contributes to early Parkinson’s onset and accelerated progression rates.

Study Design:

Understanding the role of glycosphingolipids in Parkinson’s is difficult due to structural complexity of these lipids and their changing dynamics. We will utilize a high-resolving, three-dimensional approach to measure content, turnover rate and localization of brain glycosphingolipids in Parkinson’s pre-clinical models and patient brain tissues. We will determine whether certain glycosphingolipids stand out in specific brain regions in diseased tissues and will test pharmacological treatments 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 Parkinson’s and in what ways we can restore lipid imbalances for Parkinson’s 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, formation rate and brain localization in Parkinson’s pathology. Understanding abnormal glycosphingolipid in specific brain regions in Parkinson’s patients will lay the foundation for future studies to identify new biomarkers and therapeutic avenues for the treatment of Parkinson’s.

Next Steps for Development:

Characterizing new potential targets and screening of therapeutic compounds could be undertaken using the current experimental setup in order to identify more selective targets and compounds that would lessen or reverse the disease-associated effects of glycosphingolipids. This may open up new strategies to identify novel biomarkers and new therapeutic targets for the treatment of Parkinson’s.

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