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Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain

ABSTRACT: Neuroimmune interactions mediate intercellular communication and underlie critical brain functions. Microglia, CNS-resident macrophages, modulate the brain through direct physical interactions and the secretion of molecules. One such secreted factor, the complement protein C1q, contributes to complement-mediated synapse elimination in development and disease models, yet brain C1q protein levels increase significantly throughout aging. How age-related C1q affects neuronal function has not been demonstrated. Here we report that C1q interacts with neuronal ribonucleoprotein (RNP) complexes in an age-dependent manner. Purified C1q protein undergoes RNA-dependent liquid-liquid phase separation (LLPS) in vitro, and the interaction of C1q with neuronal RNP complexes in vivo is dependent on RNA and endocytosis. Mice lacking C1q have age-specific alterations in neuronal protein synthesis in vivo and impaired fear memory extinction. Together, our findings reveal a biophysical property of C1q that underlies RNA- and age-dependent neuronal interactions and demonstrate a unique role of C1q in critical intracellular neuronal processes.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Nicole Scott-Hewitt

LAB HEAD: Beth Stevens

PROVIDER: PXD052189 | Pride | 2024-07-01

REPOSITORIES: Pride

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	230602X_SAM11699-11704_NScottHewitt_F10.raw	Raw
	230602X_SAM11699-11704_NScottHewitt_F11.raw	Raw
	230602X_SAM11699-11704_NScottHewitt_F12.raw	Raw
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Microglial-derived C1q integrates into neuronal ribonucleoprotein complexes and impacts protein homeostasis in the aging brain

Project description:Neuroimmune interactions mediate intercellular communication and underlie critical brain functions. Microglia, CNS-resident macrophages, modulate the brain through direct physical interactions and the secretion of molecules. One such secreted factor, the complement protein C1q, contributes to complement-mediated synapse elimination in development and disease models, yet brain C1q protein levels increase significantly throughout aging. Here we report that C1q interacts with neuronal ribonucleoprotein (RNP) complexes in an age-dependent manner. Purified C1q protein undergoes RNA-dependent liquid-liquid phase separation (LLPS) in vitro, and the interaction of C1q with neuronal RNP complexes in vivo is dependent on RNA and endocytosis. Mice lacking C1q have age-specific alterations in neuronal protein synthesis in vivo and impaired fear memory extinction. Together, our findings reveal a biophysical property of C1q that underlies RNA- and age-dependent neuronal interactions and demonstrate a role of C1q in critical intracellular neuronal processes.

2024-05-21 | MSV000094818 | MassIVE

Modulation of gene expression by complement protein C1q in amyloid-beta injured neurons

Project description:Complement protein C1q is induced after injury in the brain and during Alzheimer's disease and has been shown to protect against amyloid-beta induced neuronal death. In this study, we used microarray approach to identify the pathways modulated by C1q that are associated with neuroprotection. Immature rat cortical primary neurons are treated with fibrillar amyloid-beta peptides and/or C1q for 3h before RNA extraction and hybridization on rat Affymetrix microarrays. Supplementary file: Processed/normalized, probe-level signal intensities from neurons treated with amyloid-beta or C1q. Median signal intensity used as global normalization method, done with JMP genomics (v5.0) software.

2012-12-21 | E-GEOD-28886 | biostudies-arrayexpress

Modulation of gene expression by complement protein C1q in amyloid-beta injured neurons

2012-12-21 | GSE28886 | GEO

RNA Sequencing Facilitates Quantitative Analysis of Wild Type(MRL-mpj) and MRL-lpr (PBS or MSC treated) Hippocampoal Transcriptomes

Project description:Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Complement cascades mediate synaptic pruning by microglia during early postnatal brain development. The process in NPSLE remains unclear. Here, we show that complement-coordinated elimination of synaptic terminals participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We elucidated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. Microglial engulfment of synapses explained behavioral disorders. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition then apposition of phagocytic microglia, ensuing synaptic loss and neurological disease. Minocycline-deactivated microglia, antibody-blocked C1q, or neuronal Nr4a1 restore protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlight neuronal Nr4a1 and C1q as critical components amenable to pharmacological intervention.

2022-02-23 | GSE154288 | GEO

Regulation of neuronal gene and miRNA expression by the complement protein C1q associated with neuroprotection

Project description:Identification of transcriptional profiles stimulated by the complement protein C1q in rat immature neurons associated with the C1q-dependent neuroprotection observed in vitro. Use of the unbiased whole genome microarray approach to identify genes regulated by C1q. Immature neurons grown in vitro for 3 days were stimulated with 10 nM C1q for 3h.

2011-03-07 | E-GEOD-18860 | biostudies-arrayexpress

Regulation of neuronal gene and miRNA expression by the complement protein C1q associated with neuroprotection

2011-03-07 | GSE18860 | GEO

Complement C1q-dependent synapse elimination by astrocytes in a mouse model of Alzheimer's disease

Project description:Synapse loss and glial activation are hallmarks of Alzheimer's disease (AD). In Tau P301S transgenic mice, the complement pathway contributes to neuronal damage through microglial elimination of synapses. Here, we used unbiased proteomic profiling of postsynaptic density (PSD) fractions from Tau P301S mice in C1q-WT versus C1q knockout backgrounds to identify C1q-dependent changes at synapses. Integrative multi-omics analysis revealed that astrocyte- and microglia- specific proteins are increased in Tau P301S synapse fractions with age and in a C1q-dependent manner. The same set of glial proteins (including C1q, C4, Gpnmb, and S100a4) is elevated in human AD synaptic fractions, and C4 levels are raised in cerebrospinal fluid (CSF) from AD patients. Besides microglia, we show that astrocytes contribute substantially to excitatory and inhibitory synapse engulfment in Tau P301S hippocampus. Based on staining of synapse markers within lysosomes, astrocytes showed preference for excitatory synapses whereas microglia preferred to engulf inhibitory synapse markers. Genetic deletion of C1q reduced astrocytic eating of excitatory and inhibitory synapses in Tau P301S mice, and rescued synapse density. Together, our data indicate that astrocytes contact and phagocytose synapses in a C1q- dependent manner and thereby contribute to synapse loss and neurodegeneration in AD.

2021-11-03 | MSV000088313 | MassIVE

A tick C1q protein alters infectivity of the Lyme disease agent by modulating interferon γ

Project description:To understand the immunomodulation roles of complement C1q-like protein 3 (IsC1ql3), we utilized RNA sequencing (RNA-seq) to investigate the effect of IsC1ql3 on the murine transcriptome.

2023-02-01 | GSE207307 | GEO

Complement Factor H deficiency results in decreased neuroretinal expression of Cd59a in aged mice.

Project description:Purpose: The complement system is closely linked to the pathogenesis of age-related macular degeneration (AMD). Several complement genes are expressed in retinal pigment epithelium (RPE), and complement proteins accumulate in drusen. Further, a common variant of complement factor H (CFH) confers increased risk of developing AMD. Because the mechanisms by which changes in the function of CFH influence development of AMD are unclear, we examined ocular complement expression as a consequence of age in control and CFH null mutant mice. Methods: Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- C57BL/6J mice was analysed by microarrays. Expression of a wide range of complement genes was compared to expression in splenocytes and in liver tissue by qRT-PCR. Results: An age-associated increased expression of complement, particularly C1q, C3 and Factor B, in the RPE/choroid coincided with increased expression of the negative regulators Cfh and Cd59a in the neuroretina. Young mice deficient in CFH expressed Cd59a similar to WT, but failed to upregulate Cd59a expression with age. Both hepatic and splenic expression of Cd59a increased with age regardless of Cfh genotype. Conclusions: While the connection between CFH deficiency and failure to up-regulate CD59a remains unknown, these results suggest that expression of CD59 is tissue-specific and that neuroretinal regulation depends on CFH. This could contribute to the visual functional deficits and morphological changes in the Cfh-/- mouse retina that occur with age, and further suggests that deficient neuroretinal regulation of complement could represent an early event in AMD. Gene expression in neuroretinas and RPE/choroid from young and aged WT and Cfh-/- mice, 4 biological replicates in each group.

2012-10-02 | E-GEOD-38671 | biostudies-arrayexpress

Bulk RNAseq of C1Q knockout TauP301S hippocampi

Project description:The effect of C1q knockout on brain gene expression was examined in non-transgenic and TauP301S mice. Complement pathway has been shown to play an important role in neurodegenerative diseases, and in-house data show that C1QC KO protects against neurodegeneration in Alzheimer's disease (AD) model. TauP301S mice have neuroinflammation and neurodegeneration in the brain and is AD model. The most severe pathology of this disease model is in hippocampus.

2022-07-16 | GSE186414 | GEO

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