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Novel 1-hydroxypyridin-2-one metal chelators prevent and res-cue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease

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Version 2 2023-06-12, 09:22
Version 1 2023-06-09, 20:36
journal contribution
posted on 2023-06-12, 09:22 authored by Frank W Lewis, Safiya Fairooz, Joanna L Elson, Véronique Hubscher-Bruder, Jeremy Brandel, Meera Soundararajan, David Smith, David T Dexter, David Tétard, Ilse Pienaar
Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal de-generation 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 oxi-dative stress and promoting protein aggregation. We demonstrate the neuroprotec-tive 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 de-monstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced a-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 neuropatho-logical hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity.

Funding

A Researcher Mobility Grant; N.A. (not held at Sussex); The Royal Society of Chemistry

History

Publication status

  • Published

File Version

  • Published version

Journal

Archives of Toxicology

ISSN

0340-5761

Publisher

Spinger

Page range

1-19

Department affiliated with

  • BSMS Neuroscience Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2020-02-14

First Open Access (FOA) Date

2020-02-26

First Compliant Deposit (FCD) Date

2020-02-13

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