Study Rationale:
Directly targeting the toxic aggregation of α-synuclein by drugs is very challenging. However, this protein is modified by different chemical groups that have the potential to alter the aggregation processes that drive Parkinson’s disease. One such modification is a sugar, called O-GlcNAc, which has been found at several different positions on α-synuclein in human and mouse brains. Work from this lab has demonstrated that O-GlcNAc inhibits/alters α-synuclein aggregation in the test tube. Additionally, several inhibitors that increase O-GlcNAc levels in the brain are in clinical development, raising the possibility that these drugs may be potential Parkinson’s therapeutics.
Hypothesis:
We hypothesize that O-GlcNAc modifications will be different in healthy and Parkinson’s brains, either on many proteins, soluble/aggregated α-synuclein, or even at specific sites on α-synuclein and that these changes contribute to α-synuclein pathology.
Study Design:
To test this hypothesis, we will analyze brain samples from Parkinson’s patients and healthy controls. We will apply chemical and analytical tools to measure O-GlcNAc at three different levels. We will look agnostically at O-GlcNAc on overall brain proteins, compare O-GlcNAc levels on soluble and/or aggregated α-synuclein and determine which positions on α-synuclein are O-GlcNAc modified and how they each change.
Impact on Diagnosis/Treatment of Parkinson’s disease:
If successful, we believe that our results will provide strong support for the application of inhibitors that raise O-GlcNAc in Parkinson’s disease. Notably, several of these compounds, or OGA inhibitors, have already been through phase I testing and are safe and biochemically effective. Our results will also potentially identify key O-GlcNAc sites on α-synuclein for biomarker development, as well as O-GlcNAc on other proteins for follow up biochemical studies.
Next Steps for Development:
Several companies have OGA inhibitors that could be repurposed for Parkinson’s disease clinical trials. Positive results from our proposed work could lead to additional industrial investment in these compounds and the further development of biomarkers and assays to facilitate their translation to the treatment of Parkinson’s.