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Lookup NU author(s): Dr Joanna Elson, Dr Meera Soundararajan, Dr Ilse Pienaar
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal degeneration in Parkinson's disease (PD); however, a link between these features remains unconfirmed. By using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxidative stress and promoting protein aggregation. We demonstrate the neuroprotective potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds’ iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also demonstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropathological hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity.
Author(s): Lewis FW, Fairooz S, Elson JL, Hubscher-Bruder V, Brandel J, Soundararajan M, Smith D, Dexter DT, Tétard D, Pienaar IS
Publication type: Article
Publication status: Published
Journal: Archives of Toxicology
Year: 2020
Volume: 94
Pages: 813-831
Print publication date: 01/03/2020
Online publication date: 20/02/2020
Acceptance date: 11/02/2020
Date deposited: 28/02/2020
ISSN (print): 0340-5761
ISSN (electronic): 1432-0738
Publisher: Springer Nature
URL: https://doi.org/10.1007/s00204-020-02672-y
DOI: 10.1007/s00204-020-02672-y
PubMed id: 32078022
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