Inhibition of the Parkinson's Disease-Related Protein DJ-1 by Endogenous Neurotoxins of the 1,2,3,4-Tetrahydroisoquinoline Family

• Published in: ACS chemical neuroscience 2025-02
• Main Authors: Laurent, Catherine, Poncet, Gabrielle, Herskovits, Tristan, Alves de Sousa, Rodolphe, Le Corre, Laurent, Al-Azzani, Mohammed, Koenig, Annekatrin, Birman, Serge, Outeiro, Tiago Fleming, Mansuy, Daniel, Dairou, Julien
• Format: Article
• Language: English
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/acschemneuro.4c00559

The protein DJ-1 appears to play a protective role in the development of Parkinson's disease (PD). Here, we show that endogenous neurotoxins of the 1,2,3,4-tetrahydroisoquinoline family (TIQs), formed upon reaction of various aldehydes such as methylglyoxal (MGO) with the neurotransmitter dopamine, act as irreversible inhibitors of the esterase activity of human DJ-1, with IC50 values between 15 and 57 μM. The presence of a catechol function appears to be essential for these inhibitory effects, which may be at the origin of the oxidation of cysteine 106, a crucial residue in the DJ-1 active site, thereby leading to DJ-1 inhibition. We also show that these endogenous neurotoxins inhibit the protective effects of DJ-1 against glycated guanosine diphosphate (GDP) formation and against alpha-synuclein (aSyn) aggregation induced by MGO. In total, the observed inhibition of DJ-1 by these endogenous neurotoxins may contribute to their damaging effects on the nervous system and, should be taken into account in therapeutic strategies for PD and related disorders.