Study Rationale:
It is well known that the alpha-synuclein protein clumps in the cells of people with Parkinson's disease (PD), but it is unclear what prompts it to clump. Researchers believe that in PD the structure and amount of alpha-synuclein molecules differs from that in healthy cells, and these differences make alpha-synuclein in PD sticky, i.e., prone to clumping. We will use the MJF-14 antibodies -- proteins that can attach to alpha-synuclein and act as a label -- to study alpha-synuclein that has become sticky but not yet started to clump. Combined with other research techniques, these antibodies will help us compare sticky alpha-synuclein in brain samples from individuals with and without PD to identify early causes of disease.
Hypothesis:
We hypothesize that sticky alpha-synuclein accumulates in nerve cells in vulnerable brain regions earlier than first alpha-synuclein clumps -- the recognized sign of disease -- appear. If correct, this hypothesis will explain symptoms arising from brain regions with little to no apparent alpha-synuclein-related damage.
Study Design:
Tissue samples from different brain regions will be collected from individuals with PD at different stages, with multiple system atrophy (another neurodegenerative disease) or without a neurodegenerative disease. We will then use antibodies to label sticky alpha-synuclein and some other cell parts, which will allow us to see our findings under the microscope and measure the amount of alpha-synuclein in the samples. Finally, we will compare the amount of alpha-synuclein in different brain regions of people with and without PD to identify the most common and earliest changes in the brain and determine which of them can serve as reliable disease signs.
Impact on Diagnosis/Treatment of Parkinson's disease:
Knowing how the neurodegenerative processes in Parkinson's disease affects the brain tissue will help us to better understand symptoms and find a cure sooner.
Next Steps for Development:
If successful, we will prove that sticky alpha-synuclein is the earliest known and the most important cause of disease. We might also be able to show that glia -- the cells that create and maintain the brain environment -- are also involved in PD. These findings can set the stage for the development of new therapies acting on these targets.