Lina Dinkel, Selina Hummel, Valerio Zenatti, Mariagiovanna Malara, Yannik Tillmann, Alessio Colombo, Laura Sebastian Monasor, Jung H. Suh, Todd Logan, Stefan Roth, Lars Paeger, Patricia Hoffelner, Oliver Bludau, Andree Schmidt, Stephan A. Müller, Martina Schifferer, Brigitte Nuscher, Jasenka Rudan Njavro, Matthias Prestel, Laura M. Bartos, Karin Wind-Mark, Luna Slemann, Leonie Hoermann, Sebastian T. Kunte, Johannes Gnörich, Simon Lindner, Mikael Simons, Jochen Herms, Dominik Paquet, Stefan F. Lichtenthaler, Peter Bartenstein, Nicolai Franzmeier, Arthur Liesz, Antje Grosche, Tatiana Bremova-Ertl, Claudia Catarino, Skadi Beblo, Caroline Bergner, Susanne A. Schneider, Michael Strupp, Gilbert Di Paolo, Matthias Brendel, Sabina Tahirovic
{"title":"Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease","authors":"Lina Dinkel, Selina Hummel, Valerio Zenatti, Mariagiovanna Malara, Yannik Tillmann, Alessio Colombo, Laura Sebastian Monasor, Jung H. Suh, Todd Logan, Stefan Roth, Lars Paeger, Patricia Hoffelner, Oliver Bludau, Andree Schmidt, Stephan A. Müller, Martina Schifferer, Brigitte Nuscher, Jasenka Rudan Njavro, Matthias Prestel, Laura M. Bartos, Karin Wind-Mark, Luna Slemann, Leonie Hoermann, Sebastian T. Kunte, Johannes Gnörich, Simon Lindner, Mikael Simons, Jochen Herms, Dominik Paquet, Stefan F. Lichtenthaler, Peter Bartenstein, Nicolai Franzmeier, Arthur Liesz, Antje Grosche, Tatiana Bremova-Ertl, Claudia Catarino, Skadi Beblo, Caroline Bergner, Susanne A. Schneider, Michael Strupp, Gilbert Di Paolo, Matthias Brendel, Sabina Tahirovic","doi":"10.1126/scitranslmed.adl4616","DOIUrl":null,"url":null,"abstract":"Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the <jats:italic>NPC1</jats:italic> gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after <jats:italic>N</jats:italic> -acetyl- <jats:sc>l</jats:sc> -leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"262 1","pages":""},"PeriodicalIF":15.8000,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1126/scitranslmed.adl4616","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the NPC1 gene, causing lipid accumulation within late endosomes/lysosomes and resulting in progressive neurodegeneration. Although microglial activation precedes neuronal loss, it remains elusive whether loss of the membrane protein NPC1 in microglia actively contributes to NPC pathology. In a mouse model with depletion of NPC1 in myeloid cells, we report severe alterations in microglial lipidomic profiles, including the enrichment of bis(monoacylglycero)phosphate, increased cholesterol, and a decrease in cholesteryl esters. Lipid dyshomeostasis was associated with microglial hyperactivity, marked by an increase in translocator protein 18 kDa (TSPO). These hyperactive microglia initiated a pathological cascade resembling NPC-like phenotypes, including a shortened life span, motor impairments, astrogliosis, neuroaxonal pathology, and increased neurofilament light chain (NF-L), a neuronal injury biomarker. As observed in the mouse model, patients with NPC showed increased NF-L in the blood and microglial hyperactivity, as visualized by TSPO-PET imaging. Reduced TSPO expression in blood-derived macrophages of patients with NPC was measured after N -acetyl- l -leucine treatment, which has been recently shown to have beneficial effects in patients with NPC, suggesting that TSPO is a potential marker to monitor therapeutic interventions for NPC. Conclusively, these results demonstrate that myeloid dysfunction, driven by the loss of NPC1, contributes to NPC disease and should be further investigated for therapeutic targeting and disease monitoring.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.