Alpha-Synuclein Glycation and the Action of Anti-Diabetic Agents in Parkinson's Disease

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder with complex etiology and variable pathology. While a subset of cases is associated with single-gene mutations, the majority originates from a combination of factors we do not fully understand. Thus, understanding the underlying causes of PD is indispensable for the development of novel therapeutics. Glycation, the non-enzymatic reaction between reactive dicarbonyls and amino groups, gives rise to a variety of different reaction products known as advanced glycation end products (AGEs). AGEs accumulate over a proteins life-time, and increased levels of glycation reaction products play a role in diabetic complications. It is now also becoming evident that PD patients also display perturbed sugar metabolism and protein glycation, including that of alpha-synuclein, a key player in PD. Here, we hypothesize that anti-diabetic drugs targeting the levels of glycation precursors, or promoting the clearance of glycated proteins may also prove beneficial for PD patients.

Keywords: Glycation; Maillard-reaction; Parkinson’s disease; alpha-synuclein.

Fig.1

AGEs accumulate due to recurring or chronic hyperglycemia. The glucose transporters Glut1 and Glut3 that are expressed in the blood-brain barrier and neurons, respectively, shuttle glucose in an insulin-independent manner. In hyperglycemic conditions, intracerebral glucose levels also increase, which in turn increases glycation and AGEs accumulating especially in long-lived proteins. DM, diabetes mellitus.

Fig.2

Glycation affects aSyn conformations. aSyn is the predominant component of Lewy bodies. During the aggregation process, aSyn monomers start to assemble into dimers, oligomers, and eventually into β-sheet containing fibrils. Oligomers are currently thought to be the most toxic species. Interestingly, the levels of reactive dicarbonyls (GO, glyoxal; MGO, methylglyoxal) increase upon hyperglycemia, and may potentiate aSyn oligomerization, while inhibiting its fibrillization, and lead to the accumulation of toxic glycated aSyn oligomers.