Neurotransmitter glycation products: Interrelation between ADTIQ and the Park7/DJ-1 repair system – ADTIQ-PARK

The glycation process is initiated by a non-enzymatic reaction between sugar-derived aldehydes, such as methylglyoxal (MGO), and nucleophile groups present on biomolecules (amino or thiol). This reaction gives rise through a multistep process to a variety of products known as advanced glycation end-products (AGEs). DNA glycation is associated with increased mutation frequency, DNA strand breaks and cytotoxicity, whereas protein glycation causes the complications of diabetes and aging, primarily via adventitious formation of protein-protein crosslinks. We recently reported that the protein DJ-1/Park7 is a major deglycase that repairs glycated biomolecules. We showed that DJ-1 prevented protein and nucleotide glycation. Mutations in the DJ-1 gene (PARK7) are associated with familial forms of Parkinson’s disease (PD), the second most common neurodegenerative disease. These mutations lead to a strong deregulation of glycation homeostasis that may contribute to the development of this neurodegenerative disorder. Furthermore, several studies implicate glycation as an important process in PD pathogenesis.

While a lot is known and published concerning the glycation of macromolecules, the processes of glycation of metabolites has been very little studied, although they can often be particularly nucleophilic compounds. One of them is a neurotransmitter of particular interest in the context of PD, namely dopamine. Indeed, MGO can react with dopamine to form a tetrahydroisoquinoline called ADTIQ (1-acetyl-6,7-dihydroxyl-1,2,3,4-tetrahydroisoquinoline) that is toxic to neurons and has been originally found in the brain of Parkinson’s patients.

The ADTIQ-Park project aims to understand the interrelation between the molecule ADTIQ and the protein DJ-1/Park7, the major enzyme of the glycation repair system, with the goal to shed light on the role of glycation of neurotransmitters in PD pathogenesis. Quite recent preliminary in vitro data from our team suggests indeed that ADTIQ inhibits recombinant DJ-1 activity and that, reciprocally, DJ-1 inhibits ADTIQ formation.

In the ADTIQPARK project, we will study dopamine glycation and the interrelation of the derived glycation product(s) with DJ-1 in the Drosophila and mouse models. We will answer successively the following questions:
• Can DJ-1 control ADTIQ formation in vitro and accumulation in vivo, and can ADTIQ control DJ-1 activity in vitro and in vivo?
• Does ADTIQ accumulation contribute to aging and to PD-related neurodegeneration in vivo?

To this end, we would like to combine the complementary expertise of Julien Dairou (Université de Paris) and Serge Birman (ESPCI Paris, Université PSL) teams, and their collaborator Pr. Tiago Outeiro (at the University Medical Center of Göttingen, in Germany) to carry out in-depth interdisciplinary studies on the effects of ADTIQ on the glycation repair system, and the reciprocal effects of DJ-1 on the formation and neurotoxic effects of ADTIQ. We expect that the completion of this program will shed light on the role of glycation of neurotransmitters, in particular dopamine, in physiopathological processes such as aging, hyperglycemia or PD.