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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\u00a0chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds\u2019 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 \u03b1-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe<jats:sup>3+<\/jats:sup> and display a 3:1 HOPO:Fe<jats:sup>3+<\/jats:sup> 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.<\/jats:p>","DOI":"10.1007\/s00204-020-02672-y","type":"journal-article","created":{"date-parts":[[2020,2,20]],"date-time":"2020-02-20T13:03:34Z","timestamp":1582203814000},"page":"813-831","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson\u2019s disease"],"prefix":"10.1007","volume":"94","author":[{"given":"Frank W.","family":"Lewis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safiya","family":"Fairooz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna L.","family":"Elson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Hubscher-Bruder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Brandel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meera","family":"Soundararajan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T.","family":"Dexter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"T\u00e9tard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6507-9563","authenticated-orcid":false,"given":"Ilse S.","family":"Pienaar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,20]]},"reference":[{"key":"2672_CR1","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0896-6273(00)80886-7","volume":"25","author":"A Abeliovich","year":"2000","unstructured":"Abeliovich A et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. 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