Myeloid cell–specific loss of NPC1 in mice recapitulates microgliosis and neurodegeneration in patients with Niemann-Pick type C disease
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.
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- Authors
- Dinkel, L., Hummel, S., Zenatti, V., Malara, M., Tillmann, Y., Colombo, A., Monasor, L. S., Suh, J. H., Logan, T., Roth, S., Paeger, L., Hoffelner, P., Bludau, O., Schmidt, A., Müller, S. A., Schifferer, M., Nuscher, B., Njavro, J. R., Prestel, M., Bartos, L. M., Wind-Mark, K., Slemann, L., Hoermann, L., Kunte, S. T., Gnörich, J., Lindner, S., Simons, M., Herms, J., Paquet, D., Lichtenthaler, S. F., Bartenstein, P., Franzmeier, N., Liesz, A., Grosche, A., Bremova-Ertl, T., Catarino, C., Beblo, S., Bergner, C., Schneider, S. A., Strupp, M., Di Paolo, G., Brendel, M., & Tahirovic, S.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- LMU Klinikum (DE)
- German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany.
- Denali Therapeutics (United States) (US)
- Ludwig-Maximilians-Universität München (DE)
- Department of Neurology, LMU University Hospital, LMU Munich, 81377 Munich, Germany.
- University Hospital Leipzig (DE)
- Denali Therapeutics Inc., South San Francisco, CA 94080, USA.
- Corresponding author
- Dinkel, Lina
- Hummel, Selina
- Brendel, Matthias
- ORCID
- Dinkel, Lina
- Hummel, Selina
- Zenatti, Valerio
- Malara, Mariagiovanna
- Tillmann, Yannik
- Colombo, Alessio
- Monasor, Laura Sebastian
- Suh, Jung H.
- Logan, Todd
- Roth, Stefan
- Paeger, Lars
- Hoffelner, Patricia
- Bludau, Oliver
- Schmidt, Andree
- Müller, Stephan A.
- Schifferer, Martina
- Nuscher, Brigitte
- Prestel, Matthias
- Bartos, Laura M.
- Wind-Mark, Karin
- Hoermann, Leonie
- Kunte, Sebastian T.
- Gnörich, Johannes
- Lindner, Simon
- Simons, Mikael
- Herms, Jochen
- Paquet, Dominik
- Lichtenthaler, Stefan F.
- Bartenstein, Peter
- Franzmeier, Nicolai
- Liesz, Arthur
- Grosche, Antje
- Bremova-Ertl, Tatiana
- Catarino, Claudia
- Beblo, Skadi
- Bergner, Caroline
- Schneider, Susanne A.
- Strupp, Michael
- Di Paolo, Gilbert
- Brendel, Matthias
- Tahirovic, Sabina
- Venue
- Science Translational Medicine
- Published
- 2024-12-04
- Volume
- 16
- Issue
- 776
- Pages
- eadl4616-eadl4616
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W4405022609
- Semantic Scholar
- 16182b064794d64f71a2953ecc11fe5bf677141d
- Cited by
- 22
- References
- 101
- Citations by year
- 2026: 9 · 2025: 13
- FWCI
- 5.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- DZNE Pub (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- Niemann-Pick disease type C, NPC1, microglia, lysosomal storage disease, cholesterol, cholesterol esters, bis(monoacylglycero)phosphate, translocator protein (TSPO), TSPO PET imaging, neurodegeneration, neurofilament light chain, astrocyte activation, N-acetyl-L-leucine, disease biomarkers
- MeSH terms
- Niemann-Pick C1 Protein, Animals, Disease Models, Animal, Gliosis, Humans, Microglia, Receptors, GABA, Myeloid Cells, Intracellular Signaling Peptides and Proteins, Mice, Niemann-Pick Disease, Type C
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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