Loss of striatal astrocyte u-crystallin (Crym) contributes to early stage Huntington’s disease pathophysiology
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE333370 | GEO | 2026/09/28
REPOSITORIES: GEO
Similar Datasets
Project description:Crym has been shown to be expressed predominantly in striatal astrocytes and to participate in perseverative behavior. However, the function of this gene in pathological context remains unknown. Crym was found downregulated in Huntington's disease in Human and mouse model. To investigate the role of Crym in this context, we restored Crym expression by over-expressing it in NCAR and R6/2 mice. Co-expression with Rpl22-HA allowed us to assess transcriptionnal dysregulation in R6/2 mice and transcritpionnal rescue after Crym restoration.
2026-09-28 | GSE310059 | GEO
Project description:We overexpressed Rpl22-HA in astrocytes of the mouse striatum in both wild type (WT) mice and in Crym KO mice at five months of age. Crym has been shown to be expressed predominantly in striatum and is highly expressed in astrocytes, however the function of this protein in astrocytes is unknown.
2023-04-03 | GSE228506 | GEO
Project description:Striatal astrocyte Crym KO transcriptome
| PRJNA950070 | ENA
Project description:Emerging evidence increasingly indicates that astrocytes are involved in neuropsychiatric disorders, including addiction, but the cocaine-induced astrocyte transcriptome has yet to be investigated. We performed RNA-sequencing on whole-cell sorted astrocytes from the nucleus accumbens and bioinformatically characterized the astrocyte transcriptome following cocaine self-administration in male mice. We found that astrocytes exhibit robust and contextually-specific transcriptional signatures that implicate CREB as a cocaine-induced transcriptional regulator in astrocytes. CUT&RUN-sequencing revealed increased astrocytic CREB DNA binding in response to cocaine. Viral-mediated manipulation of NAc astrocytic CREB activity in combination with addiction-related behaviors revealed that astrocytic CREB increases the rewarding and reinforcing properties of cocaine. Furthermore, we identified potential molecular mechanisms of astrocytic CREB’s influence through modulating astrocytic calcium dynamics and selectively increasing D1-type medium spiny neuronal activity.
2025-09-24 | GSE308399 | GEO
Project description:Huntington’s disease (HD) is caused by expanded CAG repeats in the Huntingtin gene (HTT) that results in expression of mutant HTT proteins (mHTT) with extended polyglutamine tracts in diverse cells of the body, including striatal neurons and astrocytes. The relative contributions of neurons and astrocytes to disease pathogenesis are unknown for HD and other neurodegenerative diseases. This is a critical issue to address since it has been proposed that neuronal loss in HD and other major neurodegenerative diseases is downstream of astrocytic dysfunction that drives neuronal death. Moreover, astrocyte-to-neuron conversion is considered a promising approach in HD and other neurodegenerative diseases with little reported detriment with regards to normal astrocytic physiological functions, which are varied and extensive in health and disease. Thus, astrocytes are considered both causative and also largely replaceable in neurodegeneration, and their basic contributions to disease pathophysiology relative to neurons remain undefined in vivo. We used genetically encoded and cell-specific zinc finger protein (ZFP) transcriptional repressors to lower mHTT and molecularly dissected neuronal and astrocytic influences on HD pathophysiology at molecular, cellular, and behavioral levels. We found that the major disease drivers were in fact neurons, with astrocytes displaying lesser loss of essential functions such as cholesterol metabolism that were downstream of greater neuronal dysfunction, which encompassed neuromodulation, synaptic, and intracellular signaling. We thus dissected the cell autonomous and non-cell autonomous mechanistic and causal contributions of both neurons and astrocytes to a complex neurodegenerative disease in vivo with wider implications for rescue and repair strategies.
2022-12-15 | PXD030021 | Pride
Project description:To identify how mu-crystallin operates within striatal astrocytes, we used proximity-dependent biotinylation with BioID2 to identify mu-crystallin interacting proteins relative to GFP controls. Strong biotinylation in vivo permitted identification of the 78-protein mu-crystallin interactome, which will be fully reported in a following publication
2024-01-08 | PXD040991 | Pride
Project description:Huntington disease (HD) is an incurable neurodegenerative disease that is characterized by neuronal loss and astrogliosis. One hallmark of HD is the selective neuronal vulnerability of striatal medium spiny neurons and to date, the underlying mechanisms of this selective vulnerability have not been fully defined. Here, we employed a multi-omic approach including single nucleus RNAseq (snRNAseq), bulk RNAseq, lipidomics, CAG repeat length measurements, and multiplexed immunofluorescence on post-mortem brain tissue from multiple brain regions of HD and control donors. We defined a signature of genes that is driven by CAG repeat length and found it enriched in astrocytic and microglial genes. Moreover, weighted gene correlation network analysis showed loss of connectivity of astrocytic and microglial modules in HD and identified modules that correlated with CAG-repeat length which further implicated inflammatory pathways and metabolism. We performed lipidomic analysis of HD and control brains and identified several lipid species that correlate with HD grade, including ceramides and very long chain fatty acids. Integration of lipidomics and bulk transcriptomics identified a consensus gene signature that correlates with HD grade and HD lipidomic abnormalities and implicated the unfolded protein response pathway. Because astrocytes are critical for brain lipid metabolism and play important roles in regulating inflammation, we analyzed our snRNAseq dataset with an emphasis on astrocyte pathology. We found two main astrocyte types that spanned multiple brain regions; these types correspond to protoplasmic astrocytes, and fibrous-like, CD44-positive astrocytes. HD pathology was differentially associated with these cell types in a region-specific manner. One protoplasmic astrocyte cluster showed high expression of metallothionein genes, the depletion of which positively correlated with the depletion of vulnerable medium spiny neuronal clusters in the caudate nucleus. We confirmed that metallothioneins were increased in cingulate HD astrocytes but were unchanged or even decreased in caudate astrocytes. We combined existing genome-wide association studies (GWAS) with a GWA study conducted on HD patients from the original Venezuelan cohort and identified a single-nucleotide polymorphism in the metallothionein gene locus associated with delayed age of onset. Functional studies found that metallothionein overexpressing astrocytes are better able to buffer glutamate and were neuroprotective of induced pluripotent stem cells-derived HD MSNs as well as against rotenone-induced neuronal death in vitro. Finally, we found that metallothionein- overexpressing astrocytes increased the phagocytic activity of microglia in vitro and increased the expression of genes involved in fatty acid binding. Together, we identified an astrocytic phenotype that is regionally-enriched in less vulnerable brain regions that can be leveraged to protect neurons in HD.
2024-06-13 | GSE242197 | GEO
Project description:Huntington disease (HD) is an incurable neurodegenerative disease that is characterized by neuronal loss and astrogliosis. One hallmark of HD is the selective neuronal vulnerability of striatal medium spiny neurons and to date, the underlying mechanisms of this selective vulnerability have not been fully defined. Here, we employed a multi-omic approach including single nucleus RNAseq (snRNAseq), bulk RNAseq, lipidomics, CAG repeat length measurements, and multiplexed immunofluorescence on post-mortem brain tissue from multiple brain regions of HD and control donors. We defined a signature of genes that is driven by CAG repeat length and found it enriched in astrocytic and microglial genes. Moreover, weighted gene correlation network analysis showed loss of connectivity of astrocytic and microglial modules in HD and identified modules that correlated with CAG-repeat length which further implicated inflammatory pathways and metabolism. We performed lipidomic analysis of HD and control brains and identified several lipid species that correlate with HD grade, including ceramides and very long chain fatty acids. Integration of lipidomics and bulk transcriptomics identified a consensus gene signature that correlates with HD grade and HD lipidomic abnormalities and implicated the unfolded protein response pathway. Because astrocytes are critical for brain lipid metabolism and play important roles in regulating inflammation, we analyzed our snRNAseq dataset with an emphasis on astrocyte pathology. We found two main astrocyte types that spanned multiple brain regions; these types correspond to protoplasmic astrocytes, and fibrous-like, CD44-positive astrocytes. HD pathology was differentially associated with these cell types in a region-specific manner. One protoplasmic astrocyte cluster showed high expression of metallothionein genes, the depletion of which positively correlated with the depletion of vulnerable medium spiny neuronal clusters in the caudate nucleus. We confirmed that metallothioneins were increased in cingulate HD astrocytes but were unchanged or even decreased in caudate astrocytes. We combined existing genome-wide association studies (GWAS) with a GWA study conducted on HD patients from the original Venezuelan cohort and identified a single-nucleotide polymorphism in the metallothionein gene locus associated with delayed age of onset. Functional studies found that metallothionein overexpressing astrocytes are better able to buffer glutamate and were neuroprotective of induced pluripotent stem cells-derived HD MSNs as well as against rotenone-induced neuronal death in vitro. Finally, we found that metallothionein- overexpressing astrocytes increased the phagocytic activity of microglia in vitro and increased the expression of genes involved in fatty acid binding. Together, we identified an astrocytic phenotype that is regionally-enriched in less vulnerable brain regions that can be leveraged to protect neurons in HD.
2024-06-13 | GSE242195 | GEO
Project description:MartínJiménez2017 - Genome-scale reconstruction of the human astrocyte metabolic network
This model is described in the article:
Genome-Scale Reconstruction
of the Human Astrocyte Metabolic Network.
Martín-Jiménez CA,
Salazar-Barreto D, Barreto GE, González J.
Front Aging Neurosci 2017; 9: 23
Abstract:
Astrocytes are the most abundant cells of the central
nervous system; they have a predominant role in maintaining
brain metabolism. In this sense, abnormal metabolic states have
been found in different neuropathological diseases.
Determination of metabolic states of astrocytes is difficult to
model using current experimental approaches given the high
number of reactions and metabolites present. Thus, genome-scale
metabolic networks derived from transcriptomic data can be used
as a framework to elucidate how astrocytes modulate human brain
metabolic states during normal conditions and in
neurodegenerative diseases. We performed a Genome-Scale
Reconstruction of the Human Astrocyte Metabolic Network with
the purpose of elucidating a significant portion of the
metabolic map of the astrocyte. This is the first global
high-quality, manually curated metabolic reconstruction network
of a human astrocyte. It includes 5,007 metabolites and 5,659
reactions distributed among 8 cell compartments,
(extracellular, cytoplasm, mitochondria, endoplasmic reticle,
Golgi apparatus, lysosome, peroxisome and nucleus). Using the
reconstructed network, the metabolic capabilities of human
astrocytes were calculated and compared both in normal and
ischemic conditions. We identified reactions activated in these
two states, which can be useful for understanding the
astrocytic pathways that are affected during brain disease.
Additionally, we also showed that the obtained flux
distributions in the model, are in accordance with
literature-based findings. Up to date, this is the most
complete representation of the human astrocyte in terms of
inclusion of genes, proteins, reactions and metabolic pathways,
being a useful guide for in-silico analysis of several
metabolic behaviors of the astrocyte during normal and
pathologic states.
This model is hosted on
BioModels Database
and identified by:
MODEL1608180000.
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To the extent possible under law, all copyright and related or
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2017-05-18 | MODEL1608180000 | BioModels
Project description:Astrocytes and neurons coexist and interact in the CNS1,2. Given that many signaling and pathological events are protein-driven, identifying astrocyte and neuron proteomes is essential for elucidating the complex protein networks that dictate their respective contributions to physiology and disease. Here, we used cell- and subcompartment-specific proximity-dependent biotinylation3 to study the proteomes of striatal astrocytes and medium spiny neurons (MSNs) in vivo. We evaluated cytosolic and plasma membrane compartments for astrocytes and MSNs, revealing how these cells differ at the protein level and in their core signaling machinery. We assessed subcellular compartments of astrocytes including end feet and processes to reveal the molecular basis of essential astrocyte signaling and homeostatic functions. Unexpectedly, SAPAP3 proteins (gene; Dlgap3) associated with obsessive compulsive disorder (OCD) and repetitive behaviors4-11 were detected at equivalent levels in striatal astrocyte and MSN plasma membrane and cytosolic compartments. Astrocytic expression was confirmed by RNA-seq, fluorescence in situ hybridization and immunohistochemistry. Furthermore, genetic rescue experiments combined with behavioral analyses and proteomics in a mouse model4 of OCD lacking SAPAP3 revealed contributions of SAPAP3 in astrocytes and MSNs to repetitive and anxiety-related OCD behaviors. Our data define how astrocytes and neurons differ at the protein level and in their major signaling pathways, how astrocyte proteomes vary between physiological subcompartments, and how specific astrocyte and neuronal molecular mechanisms contribute to a psychiatric disease. Targeting both astrocytes and neurons together is likely to be therapeutically effective in complex CNS disorders.
2023-01-13 | PXD029257 | Pride