Dataset Information

Proteomic signature of NPC1 KO microglia from conditional KO mice

ABSTRACT: Niemann-Pick type C (NPC) disease is a rare neurodegenerative disorder mainly caused by autosomal recessive mutations in Npc1 which result in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is one of the prominent pathological features, consequences of NPC1 loss on microglial function and disease outcome remain largely unknown. Here, we provide an in-depth characterization of microglial proteomic signatures and phenotypes in an NPC1-deficient (Npc1-/-) murine model. We demonstrate that microglial defects, including enhanced phagocytosis and impaired lipid trafficking, occur early in the NPC pathological cascade and precede neuronal death. Compromised microglial function during Npc1-/- mouse development is reflected by enhanced synaptic pruning and deficient turnover of myelin. Accumulation of the undigested myelin occurs mainly within multi-vesicular bodies (MVBs) of Npc1-/- microglia and not within lysosomes. This is in agreement with the impairments in recycling of myelin into lipid droplets. Macrophages of NPC patients displayed similar molecular and functional alterations as murine Npc1-/- microglia, strengthening the role of NPC1 in immune homeostasis. Generated ex vivo assays using patient macrophages are novel promising clinical tools to monitor the progression and therapeutic efficacy in NPC patients.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Microglial Cell

DISEASE(S): Niemann-pick Disease

SUBMITTER: Stephan Mueller

LAB HEAD: Stefan F. Lichtenthaler

PROVIDER: PXD019452 | Pride | 2021-02-09

REPOSITORIES: Pride

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Publications

Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia.

Colombo Alessio A Dinkel Lina L Müller Stephan A SA Sebastian Monasor Laura L Schifferer Martina M Cantuti-Castelvetri Ludovico L König Jasmin J Vidatic Lea L Bremova-Ertl Tatiana T Lieberman Andrew P AP Hecimovic Silva S Simons Mikael M Lichtenthaler Stefan F SF Strupp Michael M Schneider Susanne A SA Tahirovic Sabina S

Nature communications 20210224 1

Niemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced ...[more]

PMID: 33627648

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Project description:Microglia are innate immune cells of the brain that perform phagocytic and inflammatory functions in disease conditions. Transcriptomic studies of acutely-isolated microglia have provided novel insights into their molecular and functional diversity in homeostatic and neurodegenerative disease states. State-of-the-art mass spectrometric methods can comprehensively characterize proteomic alterations in microglia in neurodegenerative disorders, potentially providing novel functionally-relevant molecular insights that are not provided by transcriptomics. However, proteomic profiling of adult primary microglia in neurodegenerative disease conditions has not been performed. We performed quantitative proteomic analyses of purified CD11b+ acutely-isolated microglia adult mice in normal, acute neuroinflammatory (LPS-treatment) and chronic neurodegenerative states (5xFAD model of Alzheimer’s disease [AD]) using tandem mass tag mass spectrometry. Differential expression analyses were performed to characterize specific microglial proteomic changes in 5xFAD mice and identify overlap with LPS-induced pro-inflammatory changes. Our results were also contrasted with existing proteomic data from wild-type mouse microglia and from existing microglial transcriptomic data from wild-type and 5xFAD mice. Neuropathological validation studies of select proteins were performed in human AD and 5xFAD brains. Of 4,133 proteins identified, 187 microglial proteins were differentially expressed in the 5xFAD mouse model of AD pathology, including proteins with previously known (Apoe, Clu and Htra1) as well as previously unreported relevance to AD biology (Cotl1 and Hexb). Proteins upregulated in 5xFAD microglia shared significant overlap with pro-inflammatory changes observed in LPS-treated mice. Several proteins increased in human AD brain were also upregulated by 5xFAD microglia (Aβ peptide, Apoe, Htra1, Cotl1 and Clu). Cotl1 was identified as a novel microglia-specific marker with increased expression and strong association with AD neuropathology. Apoe protein was also detected within plaque-associated microglia in which Apoe and Aβ were highly co-localized suggesting a role for Apoe in phagocytic clearance of Aβ. We report the first comprehensive comparative proteomic study of adult mouse microglia derived from acute neuroinflammatory and AD models, representing a valuable resource to the neuroscience research community. We highlight shared and unique microglial proteomic changes in acute neuroinflammatory, aging and AD mouse models in addition to identifying novel roles for microglial proteins in human neurodegeneration.

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