Altered expression of clock and clock‐controlled genes in a hSOD1‐linked amyotrophic lateral sclerosis mouse model

Killoy, Kelby M.; Pehar, Mariana; Harlan, Benjamin A.; Vargas, Marcelo R.

doi:10.1096/fj.202000386rr

Cited by 7 publications

(8 citation statements)

References 77 publications

(88 reference statements)

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“…FUS mutant astrocytes triggered MNs susceptible to excitotoxicity via AMPAR-mediated cell death (Kia et al, 2018). Clock and clock-controlled genes altered in FUS-ALS iPSC-derived astrocytes, contribute to metabolic and redox impairment (Killoy et al, 2021). In SOD1-mutant mouse models, misfolding cytoplasmic FUS accumulation in reactive astrocytes caused MN degenerative death via pro-inflammatory and neurotoxic pathways such as TNF-α with neutralizing antibodies (Li et al, 2016).…”

Section: Fused In Sarcoma Gene and Astrocytesmentioning

confidence: 99%

Astrocytes in Neurodegeneration: Inspiration From Genetics

Huang

Shang

2022

Front. Neurosci.

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Despite the discovery of numerous molecules and pathologies, the pathophysiology of various neurodegenerative diseases remains unknown. Genetics participates in the pathogenesis of neurodegeneration. Neural dysfunction, which is thought to be a cell-autonomous mechanism, is insufficient to explain the development of neurodegenerative disease, implying that other cells surrounding or related to neurons, such as glial cells, are involved in the pathogenesis. As the primary component of glial cells, astrocytes play a variety of roles in the maintenance of physiological functions in neurons and other glial cells. The pathophysiology of neurodegeneration is also influenced by reactive astrogliosis in response to central nervous system (CNS) injuries. Furthermore, those risk-gene variants identified in neurodegenerations are involved in astrocyte activation and senescence. In this review, we summarized the relationships between gene variants and astrocytes in four neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Parkinson’s disease (PD), and provided insights into the implications of astrocytes in the neurodegenerations.

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Section: Fused In Sarcoma Gene and Astrocytesmentioning

confidence: 99%

Astrocytes in Neurodegeneration: Inspiration From Genetics

Huang

Shang

2022

Front. Neurosci.

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“…NR1D1 downregulation in the spinal cord of these two ALS models does not seem to be restricted to a specific cell type. However, since NR1D1 displays altered rhythmicity in iPSC-derived astrocytes from ALS patients 31 and decreased NR1D1 expression can lead to dysregulated inflammation, 13,37 we sought to determine the effects of decreasing NR1D1 expression on the inflammatory profile of spinal cord astrocytes in culture. We transfected primary nontransgenic astrocyte cultures with a negative control siRNA (NC-siRNA) or an Nr1d1-specific siRNA (Nr1d1-siRNA).…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown evidence of dysregulated clock and clock‐controlled gene expression at mRNA level in early symptomatic animal models of ALS 31 . Here, we examined NR1D1 expression in the spinal cord of overtly symptomatic hSOD1 G93A mice (about 140‐day‐old).…”

Section: Resultsmentioning

confidence: 99%

“…[24][25][26][27][28][29][30] We recently analyzed the expression of clock and clock-controlled genes in multiple tissues from mutant hSOD1-linked ALS mouse models. 31 Interestingly, NR1D1 was the only core clock gene that displayed significant expression changes in all tissue types analyzed from early symptomatic mice overexpressing the ALSlinked hSOD1 G93A mutation. Here we further explore NR1D1 dysregulation in the spinal cord of ALS mouse models and its consequences on astrocyte-motor neuron interaction.…”

Section: Introductionmentioning

confidence: 94%

“…We recently analyzed the expression of clock and clock‐controlled genes in multiple tissues from mutant hSOD1‐linked ALS mouse models 31 . Interestingly, NR1D1 was the only core clock gene that displayed significant expression changes in all tissue types analyzed from early symptomatic mice overexpressing the ALS‐linked hSOD1 G93A mutation.…”

Section: Introductionmentioning

confidence: 99%

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NR1D1 downregulation in astrocytes induces a phenotype that is detrimental to cocultured motor neurons

et al. 2022

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Nuclear receptor subfamily 1 group D member 1 (NR1D1, also known as Rev‐erbα) is a nuclear transcription factor that is part of the molecular clock encoding circadian rhythms and may link daily rhythms with metabolism and inflammation. NR1D1, unlike most nuclear receptors, lacks a ligand‐dependent activation function domain 2 and is a constitutive transcriptional repressor. Amyotrophic lateral sclerosis (ALS) is the most common adult‐onset motor neuron disease, caused by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. Approximately 10%–20% of familial ALS is caused by a toxic gain‐of‐function induced by mutations of the Cu/Zn superoxide dismutase (SOD1). Dysregulated clock and clock‐controlled gene expression occur in multiple tissues from mutant hSOD1‐linked ALS mouse models. Here we explore NR1D1 dysregulation in the spinal cord of ALS mouse models and its consequences on astrocyte–motor neuron interaction. NR1D1 protein and mRNA expression are significantly downregulated in the spinal cord of symptomatic mice expressing mutant hSOD1, while no changes were observed in age‐matched animals overexpressing wild‐type hSOD1. In addition, NR1D1 downregulation in primary astrocyte cultures induces a pro‐inflammatory phenotype and decreases the survival of cocultured motor neurons. NR1D1 orchestrates the cross talk between physiological pathways identified to be disrupted in ALS (e.g., metabolism, inflammation, redox homeostasis, and circadian rhythms) and we observed that downregulation of NR1D1 alters astrocyte–motor neuron interaction. Our results suggest that NR1D1 could be a potential therapeutic target to prevent astrocyte‐mediated motor neuron toxicity in ALS.

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FABP7 drives an inflammatory response in human astrocytes and is upregulated in Alzheimer’s disease

Hamilton,

Kinscherf,

Balmer

et al. 2023

GeroScience

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Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by the accumulation of intracellular neurofibrillary tangles, extracellular amyloid plaques, and neuroinflammation. In partnership with microglial cells, astrocytes are key players in the regulation of neuroinflammation. Fatty acid binding protein 7 (FABP7) belongs to a family of conserved proteins that regulate lipid metabolism, energy homeostasis, and inflammation. FABP7 expression is largely restricted to astrocytes and radial glia-like cells in the adult central nervous system. We observed that treatment of primary hippocampal astrocyte cultures with amyloid β fragment 25–35 (Aβ25–35) induces FABP7 upregulation. In addition, FABP7 expression is upregulated in the brain of APP/PS1 mice, a widely used AD mouse model. Co-immunostaining with specific astrocyte markers revealed increased FABP7 expression in astrocytes. Moreover, astrocytes surrounding amyloid plaques displayed increased FABP7 staining when compared to non-plaque-associated astrocytes. A similar result was obtained in the brain of AD patients. Whole transcriptome RNA sequencing analysis of human astrocytes differentiated from induced pluripotent stem cells (i-astrocytes) overexpressing FABP7 identified 500 transcripts with at least a 2-fold change in expression. Gene Ontology enrichment analysis identified (i) positive regulation of cytokine production and (ii) inflammatory response as the top two statistically significant overrepresented biological processes. We confirmed that wild-type FABP7 overexpression induces an NF-κB-driven inflammatory response in human i-astrocytes. On the other hand, the expression of a ligand-binding impaired mutant FABP7 did not induce NF-κB activation. Together, our results suggest that the upregulation of FABP7 in astrocytes could contribute to the neuroinflammation observed in AD.

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Altered expression of clock and clock‐controlled genes in a hSOD1‐linked amyotrophic lateral sclerosis mouse model

Cited by 7 publications

References 77 publications

Astrocytes in Neurodegeneration: Inspiration From Genetics

Astrocytes in Neurodegeneration: Inspiration From Genetics

NR1D1 downregulation in astrocytes induces a phenotype that is detrimental to cocultured motor neurons

FABP7 drives an inflammatory response in human astrocytes and is upregulated in Alzheimer’s disease

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