Evidence Against a Role for the Parkinsonism-associated Protein DJ-1 in Methylglyoxal Detoxification

Daniel H Pfaff,Thomas Fleming,Peter Nawroth,Aurelio A Teleman

doi:10.1074/jbc.m116.743823

Abstract

Methylglyoxal (MG) is a reactive metabolite that forms adducts on cysteine, lysine and arginine residues of proteins, thereby affecting their function. Methylglyoxal is detoxified by the Glyoxalase system, consisting of two enzymes, Glo1 and Glo2, that act sequentially to convert MG into d-lactate. Recently, the Parkinsonism-associated protein DJ-1 was described in vitro to have glyoxalase activity, thereby detoxifying the MG metabolite, or deglycase activity, thereby removing the adduct formed by MG on proteins. Since Drosophila is an established model system to study signaling, neurodegeneration, and metabolic regulation in vivo, we asked whether DJ-1 contributes to MG detoxification in vivo Using both DJ-1 knockdown in Drosophila cells in culture, and DJ-1β knock-out flies, we could detect no contribution of DJ-1 to survival to MG challenge or to accumulation of MG protein adducts. Furthermore, we provide data suggesting that the previously reported deglycation activity of DJ-1 can be ascribed to a TRIS buffer artifact.

Highlights

Methylglyoxal (MG) is a reactive metabolite that forms adducts on cysteine, lysine and arginine residues of proteins, thereby affecting their function
The connection between Parkinsonism and Diabetes mellitus has been subject to discussion for a long time, in particular because of the role of reactive metabolites in the pathogenesis of both diseases
The reported enzymatic activities of DJ-1 as a glyoxalase or a deglycase [11, 12] would create a link between these two diseases since DJ-1 has been linked to Parkinsonism and MG detoxification has been linked to diabetes [6, 10]

Summary

Introduction

Methylglyoxal (MG) is a reactive metabolite that forms adducts on cysteine, lysine and arginine residues of proteins, thereby affecting their function. While reactive oxygen species (ROS) have been linked to cancer and age-related diseases like Parkinsonism [1], reactive carbonyl species (RCS) have been linked to the pathogenesis of diabetic late complications and atherosclerosis [2, 3] One such RCS is methylglyoxal (MG), which forms as a byproduct of flux through various metabolic pathways including glycolysis [4, 5]. DJ-1 was reported to have deglycase activity in vitro, enzymatically removing early-stage methylglyoxal and glyoxal adducts from protein side-chains, thereby preventing the formation of irreversible AGEs [12] Both of these findings are intriguing, since they would place DJ-1 at the intersection between detoxification of reactive oxygen species and detoxification of reactive carbonyl species [10]. Mutation of two familial Parkinsonism genes, Pink and Parkin, in Drosophila recapitulates many of the cornerstone molecular and neurological phenotypes of Parkinson disease [13]

Methods

Results

Conclusion