Tiziana Petrozziello, Negin Jalali Motlagh, Ranee Zara B. Monsanto, Dan Lei, Micaela G. Murcar, Ellen B. Penney, D. Cristopher Bragg, Cara Fernandez-Cerado, G. Paul Legarda, Michelle Sy, Edwin Muñoz, Mark C. Ang, Cid Czarina E. Diesta, Can Zhang, Rudolph E. Tanzi, Irfan A. Qureshi, John W. Chen, Ghazaleh Sadri-Vakili
{"title":"靶向髓过氧化物酶以减轻 X-遗传性肌张力障碍性帕金森病的神经炎症","authors":"Tiziana Petrozziello, Negin Jalali Motlagh, Ranee Zara B. Monsanto, Dan Lei, Micaela G. Murcar, Ellen B. Penney, D. Cristopher Bragg, Cara Fernandez-Cerado, G. Paul Legarda, Michelle Sy, Edwin Muñoz, Mark C. Ang, Cid Czarina E. Diesta, Can Zhang, Rudolph E. Tanzi, Irfan A. Qureshi, John W. Chen, Ghazaleh Sadri-Vakili","doi":"10.1111/cns.70109","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated an increase in myeloperoxidase (MPO) levels in XDP postmortem prefrontal cortex (PFC), suggesting a role for inflammation in XDP pathogenesis. Therefore, we hypothesized that inhibiting MPO could provide a therapeutic strategy for XDP.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>MPO activity was measured by using an MPO-activatable fluorescent agent (MAFA) in human postmortem PFC. Reactive oxygen species (ROS) and MPO activity were measured in XDP-derived fibroblasts and SH-SY5Y cells following MPO inhibition.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>MPO activity was significantly increased in XDP PFC. Additionally, treatment of cell lines with postmortem XDP PFC resulted in a significant increase in ROS levels. To determine whether increases in MPO activity caused increases in ROS, MPO content was immunodepleted from XDP PFC, which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment.</p>\n </section>\n </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"30 11","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11537767/pdf/","citationCount":"0","resultStr":"{\"title\":\"Targeting Myeloperoxidase to Reduce Neuroinflammation in X-Linked Dystonia Parkinsonism\",\"authors\":\"Tiziana Petrozziello, Negin Jalali Motlagh, Ranee Zara B. Monsanto, Dan Lei, Micaela G. Murcar, Ellen B. Penney, D. Cristopher Bragg, Cara Fernandez-Cerado, G. Paul Legarda, Michelle Sy, Edwin Muñoz, Mark C. Ang, Cid Czarina E. Diesta, Can Zhang, Rudolph E. Tanzi, Irfan A. Qureshi, John W. Chen, Ghazaleh Sadri-Vakili\",\"doi\":\"10.1111/cns.70109\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Aims</h3>\\n \\n <p>Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated an increase in myeloperoxidase (MPO) levels in XDP postmortem prefrontal cortex (PFC), suggesting a role for inflammation in XDP pathogenesis. Therefore, we hypothesized that inhibiting MPO could provide a therapeutic strategy for XDP.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>MPO activity was measured by using an MPO-activatable fluorescent agent (MAFA) in human postmortem PFC. Reactive oxygen species (ROS) and MPO activity were measured in XDP-derived fibroblasts and SH-SY5Y cells following MPO inhibition.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>MPO activity was significantly increased in XDP PFC. Additionally, treatment of cell lines with postmortem XDP PFC resulted in a significant increase in ROS levels. To determine whether increases in MPO activity caused increases in ROS, MPO content was immunodepleted from XDP PFC, which resulted in a significant decrease in ROS in SH-SY5Y cells. 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Targeting Myeloperoxidase to Reduce Neuroinflammation in X-Linked Dystonia Parkinsonism
Aims
Although the genetic locus of X-linked dystonia parkinsonism (XDP), a neurodegenerative disease endemic in the Philippines, is well-characterized, the exact mechanisms leading to neuronal loss are not yet fully understood. Recently, we demonstrated an increase in myeloperoxidase (MPO) levels in XDP postmortem prefrontal cortex (PFC), suggesting a role for inflammation in XDP pathogenesis. Therefore, we hypothesized that inhibiting MPO could provide a therapeutic strategy for XDP.
Methods
MPO activity was measured by using an MPO-activatable fluorescent agent (MAFA) in human postmortem PFC. Reactive oxygen species (ROS) and MPO activity were measured in XDP-derived fibroblasts and SH-SY5Y cells following MPO inhibition.
Results
MPO activity was significantly increased in XDP PFC. Additionally, treatment of cell lines with postmortem XDP PFC resulted in a significant increase in ROS levels. To determine whether increases in MPO activity caused increases in ROS, MPO content was immunodepleted from XDP PFC, which resulted in a significant decrease in ROS in SH-SY5Y cells. Consistently, the treatment with verdiperstat, a potent and selective MPO inhibitor, significantly decreased ROS in both XDP-derived fibroblasts and XDP PFC-treated SH-SY5Y cells.
Conclusions
Collectively, our results suggest that MPO inhibition mitigates oxidative stress and may provide a novel therapeutic strategy for XDP treatment.
期刊介绍:
CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.