Study Rationale:
Genetic changes in the glucocerebrosidase (GBA) gene are linked to a higher risk of developing Parkinson's disease (PD) and dementia with Lewy bodies (DLB). These changes in GBA in nerve cells may cause an increased abundance of alpha-synuclein, the protein that forms Lewy bodies that kills nerve cells. It is unclear how changes in GBA lead to Lewy bodies and nerve cell death; solving this scientific question will point toward new treatments for PD and DLB.
Hypothesis:
It is possible that abnormalities in GBA change the process of making lipids (fats) in nerve cells and that this change cause alpha-synuclein to clump and form Lewy bodies.
Study Design:
This study will evaluate different aspects of PD biology to allow us to test our hypothesis as follows:
- We will measure different types of lipids in brain tissue obtained post-mortem from individuals with PD, DLB and healthy brain donors with genetic changes in GBA and compare these lipids to individuals with PD, DLB and healthy brain donors with normal GBA.
- Cells produce tiny particles called exosomes which allow material to pass from one cell to another. We will purify these exosomes from brain tissue and from cerebrospinal fluid (the fluid that baths the brain) and test them for alpha-synuclein and lipids. These measurements will tell us if alpha-synuclein forms clumps in exosomes and spreads within the brain; they will also tell us if lipid changes caused by abnormal GBA increase the spread of alpha-synuclein.
Impact on Diagnosis/Treatment of Parkinson's disease:
If we identify how changes in GBA cause alpha-synuclein clumps, we may be able to design ways to stop this process. The underlying cause of abnormalities in alpha-synuclein must be determined before we can develop a reliable treatment for PD.
Next Steps for Development:
Lipid abnormalities in the brain, if identified, can be targeted through pharmacological interventions. If exosomes promote clumping or spreading of alpha-synuclein, reducing exosome spreading will provide a basis for developing therapies for individuals at risk of developing PD or DLB.
Final Outcome
Glucocerebrosidase is a protein that plays a role in the cells' garbage disposal and breaks down fatty substances. Mutations (changes) in the glucocerebrosidase gene GBA1 are linked to a higher risk of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In this study, we identified differences in sphingolipids -- one type of fatty substances -- between healthy people and people with PD and DLB. One type of sphingolipids, ceramides, differed between the groups the most; however, there was no difference in ceramides between people with PD and those with GBA1-associated DLB. This indicates that these differences in ceramides are not specific to either disease and serve a marker of both. In the cerebrospinal fluid of people with PD and DLB, exosomes (small bubbles) were filled with ceramides, indicating a possible role of ceramides in the disease process. We also identified alpha-synuclein -- a protein found in Lewy bodies in PD and DLB -- inside those exosomes. As exosomes from healthy individuals also had alpha-synuclein in them, more powerful methods may help determine whether the exosomes from people with a neurodegenerative disease contain alpha-synuclein clumps, a hallmark of Parkinson's.
Cells use multiple mechanisms of ceramide production. Studying ceramide production in nerve cells in detail will help us determine what causes ceramides to accumulate in PD and DLB and identify new therapeutic targets for these diseases. Furthermore, we should study the effect of ceramide-filled exosomes on nerve cells because this might suggest new diagnostic or therapeutic strategies for PD and DLB.
February 2018