Study Rationale:
Alpha-synuclein is a sticky protein that clumps in the brains of people with Parkinson's disease (PD). Chemicals that stick to alpha-synuclein make it toxic to brain cells. Sugar-like chemical O-GlcNAc can stick to alpha-synuclein in several different places. We have found that several of these O-GlcNAc attachments, also called modifications, on the contrary, slow or change alpha-synuclein clumping in the test tube, raising the possibility that greater modification of alpha-synuclein with O-GlcNAc could protect the brain from damage and have a therapeutic potential in PD.
Hypothesis:
We hypothesize that the alpha-synuclein clumps modified with O-GlcNAcylated are less toxic to brain cells than clumps without modifications and that there is an important link between the structure of the clump and its toxicity. We also hypothesize that toxicity can be changed by these sugar modifications in the brain.
Study Design:
To test this hypothesis, we used chemistry methods to produce alpha-synuclein with a specific O-GlcNAc modification and demonstrated that it does indeed clump differently. We will now simultaneously determine how this modification changes the fine structure of the clumps and whether it makes the clumps more or less toxic to brain cells in the test tube and in pre-clinical models.
Impact on Diagnosis/Treatment of Parkinson's Disease:
We believe that the outcomes of this study will expand our knowledge in two important ways that could impact Parkinson's treatment. First, because O-GlcNAc is found attached to alpha-synuclein in the human brain, it is possible that treatments increasing or maintaining this modification may slow the production of toxic clumps. Second, we still know very little about why alpha-synuclein clumps are toxic, and we believe our studies of their structure will provide new answers to this important question.
Next Steps for Development:
The next steps include a study of whether the number of O-GlcNAc modifications on alpha-synuclein can be changed in pre-clinical models. This would reveal the potential for increasing O-GlcNAc modifications in people with Parkinson's and for the development of other types of therapeutics that "push" alpha-synuclein to clump in a less toxic way.