Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease

Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the <i>NPC1</i> 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 <i>N</i>-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.

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Journal
Science Translational Medicine
Published
2024-12-04
DOI
https://doi.org/10.1126/scitranslmed.adl4616
Citations
17
Primary Topic
Lysosomal Storage Disorders Research
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article
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5.55
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article

Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease

Lars Paeger, Dominik Paquet, Antje Grosche, Arthur Liesz et al.
17 citations
Science Translational Medicine
Lysosomal Storage Disorders Research
5.55
article

Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease

Lars Paeger, Dominik Paquet, Antje Grosche, Arthur Liesz, Matthias Prestel, Luna Slemann, Leonie Hoermann, Laura Sebastián Monasor, Stefan Roth, T. Daniel Logan, Brigitte Nuscher, Oliver Bludau, Jasenka Rudan Njavro, Caroline G. Bergner, Peter Bartenstein, Claudia B. Catarino, Mariagiovanna Malara, Andree Schmidt, Matthias Brendel, Sabina Tahirović, Johannes Gnörich, Karin Wind-Mark, Martina Schifferer, Tatiana Brémovà-Ertl, Jochen Herms, Gilbert Di Paolo, Stefan F. Lichtenthaler, Stephan A. Müller, Michael Leo Strupp, Selina Hummel, Mikael Simons, Nicolai Franzmeier, Laura M. Bartos, Susanne A. Schneider, Skadi Beblo, Lina Dinkel, Patricia Hoffelner, Valerio Zenatti, Simon Lindner, Alessio Colombo, Yannik Tillmann, Sebastian T. Kunte, Jung H. Suh
article en
17 citations

Abstract

Niemann-Pick type C (NPC) disease is an inherited lysosomal storage disorder mainly driven by mutations in the <i>NPC1</i> 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 <i>N</i>-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.

Science Translational MedicineVol. 16(776)
University Hospital of Bern (CH), German Center for Neurodegenerative Diseases (DE), TUM Klinikum (DE), LMU Klinikum (DE), Denali Therapeutics (United States) (US), Munich Cluster for Systems Neurology (DE), University Hospital Leipzig (DE), Friedrich Baur Stiftung (DE), Bernstein Center for Computational Neuroscience Munich (DE), Technical University of Munich (DE), Ludwig-Maximilians-Universität München (DE), University of Gothenburg (SE), Leipzig University (DE)
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Openalex Percentile: Top 3%
Lysosomal Storage Disorders Research
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