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The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of this lysosomal enzyme, and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Most of the effects in the brain have been attributed to the accumulation of sulfatides in oligodendrocytes and their cell damage. In contrast, less is known regarding sulfatide toxicity in astrocytes. Poly (ADP-ribose) polymerase (PARP) inhibitors are anti-cancer therapeutics that have proven efficacy in preclinical models of many neurodegenerative and inflammatory diseases, but have never been tested for MLD. Here, we examined the toxic effect of sulfatides on human astrocytes and restoration of this cell damage by the marketed PARP-1 inhibitor, Olaparib. Cultured human astrocytes were treated with increasing concentrations of sulfatides (5\u2013100\u00a0\u03bcM) with or without Olaparib (100\u00a0nM). Cell viability assays were used to ascertain whether sulfatide-induced toxicity was rescued by Olaparib. Immunofluorescence, calcium (Ca<jats:sup>2+<\/jats:sup>) imaging, ROS, and mitochondrial damage assays were also used to explore the effects of sulfatides and Olaparib. ELISAs were performed and chemotaxis of peripheral blood immune cells was measured to examine the effects of Olaparib on sulfatide-induced inflammation in human astrocytes. Here, we established a concentration-dependent (EC<jats:sub>50<\/jats:sub>\u223c20\u00a0\u03bcM at 24\u00a0h) model of sulfatide-induced astrocyte toxicity. Our data demonstrate that sulfatide-induced astrocyte toxicity involves (i) PARP-1 activation, (ii) pro-inflammatory cytokine release, and (iii) enhanced chemoattraction of peripheral blood immune cells. Moreover, these sulfatide-induced effects were attenuated by Olaparib (IC<jats:sub>50<\/jats:sub>\u223c100\u00a0nM). In addition, sulfatide caused impairments of ROS production, mitochondrial stress, and Ca<jats:sup>2+<\/jats:sup> signaling in human astrocytes, that were indicative of metabolic alterations and that were also alleviated by Olaparib (100\u00a0nM) treatment. Our data support the hypothesis that sulfatides can drive astrocyte cell death and demonstrate that Olaparib can dampen many facets of sulfatide-induced toxicity, including, mitochondrial stress, inflammatory responses, and communication between human astrocytes and peripheral blood immune cells. These data are suggestive of potential therapeutic utility of PARP inhibitors in the sphere of rare demyelinating diseases, and in particular MLD.<\/jats:p>\n                <jats:p><jats:bold>Graphical Abstract<\/jats:bold><\/jats:p>\n                \n                <jats:p><jats:bold>Graphical abstract. Proposed mechanism of action of Olaparib in sulfatide-treated astrocytes.<\/jats:bold> Human astrocytes treated for 24\u00a0h with sulfatides increase PARP-1 expression and die. PARP-1 overexpression is modulated by Ca<jats:sup>2+<\/jats:sup> release from the endoplasmic reticulum, thus enhancing intracellular Ca<jats:sup>2+<\/jats:sup> concentration. PARP-1 inhibition with Olaparib reduces Ca<jats:sup>2+<\/jats:sup> influx and cell death. Olaparib also decreases IL-6, IL-8, IL-17, and CX3CL1 release from sulfatide-stimulated astrocytes, suggesting that PARP-1 plays a role in dampening neuroinflammation in MLD. This is confirmed by the reduction of immune cell migration such as lymphocytes, NK cells, and T cells towards sulfatide-treated astrocytes. Moreover, mitochondrial stress and ROS production induced by sulfatides are rescued by PARP-1 inhibition. Future studies will focus on the signaling cascades triggered by PARP-1-mediated currents in reactive astrocytes and Olaparib as a potential therapeutic target for MLD.<\/jats:p>","DOI":"10.1007\/s11481-023-10092-9","type":"journal-article","created":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T07:01:52Z","timestamp":1699081312000},"page":"592-609","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Elucidating the Therapeutic Utility of Olaparib in Sulfatide-Induced Human Astrocyte Toxicity and Neuroinflammation"],"prefix":"10.1007","volume":"18","author":[{"given":"Marianna","family":"Mekhaeil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Jane","family":"Conroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumlesh Kumar","family":"Dev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,4]]},"reference":[{"key":"10092_CR1","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1038\/nrn1824","volume":"7","author":"NJ Abbott","year":"2006","unstructured":"Abbott NJ, R\u00f6nnb\u00e4ck L, Hansson E (2006) Astrocyte\u2013endothelial interactions at the blood\u2013brain barrier. 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The work was performed in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans. Healthy donors provided informed consent for sample blood acquisition and the study received full ethical approval from the Faculty of Health Sciences Ethics Committee at Trinity College Dublin. Blood samples were pseudonymized to protect the privacy rights of the donors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}]}}