Parkinson's disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro

Sci Rep. 2017 Oct 9;7(1):12816. doi: 10.1038/s41598-017-13146-0.

Noriyuki Matsuda ¹ ², Mayumi Kimura ³ ⁴, Bruno Barros Queliconi ³ ⁴, Waka Kojima ³ ⁴ ⁵, Masaki Mishima ⁶, Kenji Takagi ⁷, Fumika Koyano ³, Koji Yamano ³, Tsunehiro Mizushima ⁷, Yutaka Ito ⁶, Keiji Tanaka ⁸ ⁹

Affiliations

1 Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan. matsuda-nr@igakuken.or.jp.
2 JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan. matsuda-nr@igakuken.or.jp.
3 Ubiquitin Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan.
4 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan.
5 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
6 Graduate School of Science and Engineering, Tokyo Metropolitan University, 1-1 Minamiosawa, Hachioji, 192-0397, Japan.
7 Picobiology Institute, Graduate School of Life Science, University of Hyogo, 3-2-1 Kouto, Kamighori, Ako, Hyogo, 678-1297, Japan.
8 Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya, Tokyo, 156-8506, Japan. tanaka-kj@igakuken.or.jp.
9 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan. tanaka-kj@igakuken.or.jp.

PMID: 28993701 DOI: 10.1038/s41598-017-13146-0

Abstract

DJ-1 (also known as PARK7) has been identified as a causal gene for hereditary recessive Parkinson's disease (PD). Consequently, the full elucidation of DJ-1 function will help decipher the molecular mechanisms underlying PD pathogenesis. However, because various, and sometimes inconsistent, roles for DJ-1 have been reported, the molecular function of DJ-1 remains controversial. Recently, a number of papers have suggested that DJ-1 family proteins are involved in aldehyde detoxification. We found that DJ-1 indeed converts methylglyoxal (pyruvaldehyde)-adducted glutathione (GSH) to intact GSH and lactate. Based on evidence that DJ-1 functions in mitochondrial homeostasis, we focused on the possibility that DJ-1 protects co-enzyme A (CoA) and its precursor in the CoA synthetic pathway from aldehyde attack. Here, we show that intact CoA and β-alanine, an intermediate in CoA synthesis, are recovered from methylglyoxal-adducts by recombinant DJ-1 purified from E. coli. In this process, methylglyoxal is converted to L-lactate rather than the D-lactate produced by a conventional glyoxalase. PD-related pathogenic mutations of DJ-1 (L10P, M26I, A104T, D149A, and L166P) impair or abolish detoxification activity, suggesting a pathological significance. We infer that a key to understanding the biological function of DJ-1 resides in its methylglyoxal-adduct hydrolase activity, which protects low-molecular thiols, including CoA, from aldehydes.

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