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Funded Studies

Glycosylation as an Inhibitor of Alpha-synuclein Aggregation

During the development of Parkinson’s disease the protein alpha-synuclein forms toxic clumps, or aggregates, that have been demonstrated to directly contribute to the progression of the disease. Therefore, inhibition of this aggregation process would be a significant therapeutic advance. One strategy to accomplish this goal is the development of drugs that directly block alpha-synuclein aggregation; however, these types of molecules have proven difficult to find. As an alternative strategy, we propose to take advantage of cellular-modifications of alpha-synuclein that have the potential to prevent aggregation. Specifically, the question that we ask is whether a form of glycosylation (a cellular process where a carbohydrate attaches to another molecule) termed O-GlcNAc modification, which occurs on alpha-synuclein in healthy neurons, will directly block its aggregation.

Project Description:             
To answer our straightforward question, we are taking an equally straightforward approach. We will use synthetic protein-chemistry to build alpha-synuclein with or without O-GlcNAc modification from the ground up, resulting in highly pure proteins. With these proteins in hand, we will use a variety of biophysical techniques to directly test if O-GlcNAc modification blocks alpha-synuclein aggregation. This chemical strategy will allow us to isolate the effect of O-GlcNAc modification from confounding factors that may arise in cell- or animal-models of Parkinson’s disease and lay down a firm foundation for future pre- and clinical research into exploiting O-GlcNAc modification as a therapeutic strategy.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
We hypothesize that O-GlcNAc modification will slow or completely block alpha-synuclein aggregation, strongly suggesting that increasing the amounts of this modification in the brains of Parkinson’s disease patients will slow or halt the progression of their disease. Notably, small-molecule inhibitors already exist that raise O-GlcNAc modification levels in the brains of pre-clinical models. Importantly, these inhibitors are specific and quite potent. Therefore, if our hypothesis is correct, these small molecules can be almost immediately translated into pre- and clinical testing.

Anticipated Outcome:          
At the completion of our proposed research, we predict that our data will support a role for O-GlcNAc modification in the inhibition of alpha-synuclein aggregation. As stated above, this will provide a strong biochemical rationale for the testing of drugs that increase O-GlcNAc modification in Parkinson’s disease.

Final Outcome

Alpha-synuclein is a sticky protein that clumps in the brains of people with Parkinson's disease (PD). N-acetyl-glucosamine (O-GlcNAc), a sugar-like molecule, can modify (become attached to) alpha-synuclein in a process called glycosylation. This raises the possibility that the number of modifications -- O-GlcNAc molecules attached to a single alpha-synuclein protein -- may, in turn, affect alpha-synuclein clumping. We have used chemical methods to produce alpha-synuclein with one O-GlcNAc modification. We found that this modification can completely block clumping, making alpha-synuclein less toxic in vitro. Finally, we discovered that O-GlcNAc prevents clumping by blocking the entry of new individual alpha-synuclein proteins into a growing clump. Together, these findings indicate that drugs that increase the number of O-GlcNAc modifications could slow the progression of PD.

November 2014

National Meeting of the American Chemical Society; New Orleans, LA; (2013) invited oral presentation.
National Meeting of the American Chemical Society; Dallas, TX; (2014) invited oral presentation.

Marotta NP, Lin YU, Zaro BW, et al. O-GlcNAc modification blocks the aggregation and toxicity of the protein a-synuclein associated with Parkinson's disease. Nat Chemistry. 2015;7(11):913-920.


  • Matthew R. Pratt, PhD

    Los Angeles, CA United States

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