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

LEWIS, Frank W., FAIROOZ, Safiya, ELSON, Joanna L., HUBSCHER-BRUDER, Véronique, BRANDEL, Jeremy, SOUNDARARAJAN, Meera, SMITH, David, DEXTER, David T., TÉTARD, David and PIENAAR, Ilse S. (2020). Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease. Archives of Toxicology, 94 (3), 813-831.

[img]
Preview
PDF
204_2020_Article_2672.pdf - Published Version
Creative Commons Attribution.

Download (3MB) | Preview
Open Access URL: https://link.springer.com/article/10.1007%2Fs00204... (Published version)
Link to published version:: https://doi.org/10.1007/s00204-020-02672-y
Related URLs:

    Abstract

    Abstract: 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. 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.

    Item Type: Article
    Additional Information: ** From Springer Nature via Jisc Publications Router ** Licence for this article: https://creativecommons.org/licenses/by/4.0/ **Journal IDs: pissn 0340-5761; eissn 1432-0738 **Article IDs: publisher-id: s00204-020-02672-y; manuscript: 2672 **History: published 03-2020; published_online 20-02-2020; online 20-02-2020; registration 11-02-2020; accepted 11-02-2020; submitted 28-08-2019
    Uncontrolled Keywords: In Vitro Systems, Alpha-synuclein, Dopaminergic, Iron chelators, Lactacystin, Parkinson’s disease, Reactive oxygen species
    Identification Number: https://doi.org/10.1007/s00204-020-02672-y
    Page Range: 813-831
    SWORD Depositor: Colin Knott
    Depositing User: Colin Knott
    Date Deposited: 08 Jun 2020 12:06
    Last Modified: 08 Jun 2020 12:15
    URI: http://shura.shu.ac.uk/id/eprint/26416

    Actions (login required)

    View Item View Item

    Downloads

    Downloads per month over past year

    View more statistics