Inhibition of the Parkinson’s Disease-Related Protein DJ-1 by Endogenous Neurotoxins of the 1,2,3,4-Tetrahydroisoquinoline Family
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.
Authors
- Mohammed Al‐Azzani (ORCID: https://orcid.org/0000-0003-2864-0854)
- Tiago F. Outeiro (ORCID: https://orcid.org/0000-0003-1679-1727)
- Rodolphe Alves de Sousa (ORCID: https://orcid.org/0000-0001-8815-3041)
- Theodore T. Herskovits
- Alexander Köenig (ORCID: https://orcid.org/0000-0003-0304-6242)
- Julien Dairou (ORCID: https://orcid.org/0000-0003-1767-0572)
- Laurent Le Corre (ORCID: https://orcid.org/0000-0002-0136-8072)
- Daniel Mansuy (ORCID: https://orcid.org/0000-0002-9861-1509)
- Catherine Laurent
- Serge Birman (ORCID: https://orcid.org/0000-0002-4278-454X)
- Gabrielle Poncet
Institutions
- Centre National de la Recherche Scientifique (FR)
- Université Paris Cité (FR)
- German Center for Neurodegenerative Diseases (DE)
- Universitätsmedizin Göttingen (DE)
- Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques (FR)
- Laboratoire Plasticité du Cerveau (FR)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- University of Göttingen (DE)
- Newcastle University (GB)
- ESPCI Paris (FR)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2025-02-26
- DOI
- https://doi.org/10.1021/acschemneuro.4c00559
- Citations
- 2
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 2.78
Funders
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale