For the past few years we have been studying how the age-associated process of glycation (the chemical reaction of sugar molecules with proteins) affects the aggregation and toxicity of one of the central players in Parkinson’s disease (PD), the alpha-synuclein protein. Glycation is an unavoidable process, a bit like “rusting”, since it happens spontaneously, once the levels of the glycating agents are high enough, and the targets of glycation (e.g. proteins) are in the vicinity. Neuronal cells in our brains are highly dependent on the enzymatic breakdown and metabolism of glucose for energy. Alpha-synuclein is a long-lived protein, and is known to accumulate in insoluble deposits in the brains of patients with PD and other similar disorders. The close proximity of the glucose the brain uses for energy and the alpha-synuclein protein, create an environment where glycation may happen easily.

There are studies suggesting a connection between diabetes and Parkinson’s. In diabetes, the levels of glycating agents are increased in our bodies, due to the impairments in normal sugar metabolism. The molecular underpinnings of this relationship are still unclear, but the effects of glycation on alpha-synuclein are clear. In our study recently published in the journal Brain, we first found, using cellular model systems, that alpha-synuclein is glycated in the human brain. We investigated the impact of glycation in vivo, in animal models of PD and found that glycation exacerbates alpha-synuclein toxicity.

The mechanism through which glycation exacerbates alpha-synuclein toxicity involves proteostasis (the process that regulates proteins within the cell) imbalance, impaired degradation and secretion, and conformational alterations that reduce membrane interactions. Strikingly, we showed that glycation-scavenging agents, such as aminoguanidine, protect against its detrimental effects in vivo, restoring alpha-synuclein proteostasis and ameliorating motor performance in animal models.

Altogether, our recent discoveries position glycation as an important player in PD, and opens novel perspectives for the development of drugs that might prove beneficial in interfering with the progression of PD. In addition, we predict that our study will inspire others in the field to investigate whether the mechanisms underlying the effects of glycation on alpha-synuclein are similar among different neurodegenerative diseases. In fact, we already conducted a parallel study in models of Huntington’s disease, another neurodegenerative disorder, and found identical effects, further corroborating our findings and their broad significance. Thus, we are confident we are on the right track towards a more complete understanding of the mechanisms putting us at risk for the development of PD, a path that should bring us closer to the development of novel therapeutic strategies.

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Dr. Tiago Fleming Outiero, PhD, presented at the WPC 2016 and spoke on the WPC Scientific Update 2015 webcast. He is currently Director of the Department of Experimental Neurodegeneration, University Medical Center Goettingen in Goettingen, Germany.
 

Watch his talk on the WPC Scientific Update 2015 webcast.

Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®.