Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome

Puente-Bedia, Alba; Berciano, Marı́a T.; Martı́nez-Cué, Carmen; Lafarga, Miguel; Rueda, Noemı́

doi:10.3390/antiox11122438

Cited by 8 publications

(8 citation statements)

References 140 publications

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“…Given reports of increased DNA damage and chronic neuroinflammation in DS and the Ts65Dn brain ( Guedj et al, 2016 ; Ahmed et al, 2021 ; Puente-Bedia et al, 2022 ), we hypothesized that subpopulations of Ts65Dn cells would exhibit accelerated senescence. Senescent cells accumulate in aged tissues because of exhaustion of proliferation-competent cells ( Di Micco et al, 2021 ; Kumari and Jat, 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Single-Nucleus Profiling Identifies Accelerated Oligodendrocyte Precursor Cell Senescence in a Mouse Model of Down Syndrome

Rusu

Kukreja

et al. 2023

eNeuro

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Down Syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive deficits. However, the mechanisms by which triplication of chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus ATAC and RNA-sequencing (snATAC-seq and snRNA-seq) analysis of the adult cortex. We identified cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discovered enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We found that senescence is restricted to a subset of OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescued cortical OPC proliferation, restored microglial homeostasis, and improved contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS.SIGNIFICANCE STATEMENTDown Syndrome (DS) is the most common genetic cause of intellectual disability worldwide, is characterized by chronic neuroinflammation, and results in a ubiquitous incidence of early-onset neurodegeneration. Here, we conduct single-nucleus multi-omic profiling of the mature adult cortex of an established mouse model of DS, and systematically identify key perturbations in pathways critical for neurogenesis, myelination, and neuroinflammation. We discover the enrichment of a senescence- associated gene signature in trisomic cortical oligodendrocyte precursor cells (OPCs), validate our computational findings using orthogonal approaches, and show that a senescence-reducing flavonoid significantly improves memory deficits. Our findings suggest that OPC senescence may play a role in the pathogenesis of DS and that senescence-reducing treatment may provide a novel approach for improving cognitive dysfunction in DS.

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Section: Resultsmentioning

confidence: 99%

Single-Nucleus Profiling Identifies Accelerated Oligodendrocyte Precursor Cell Senescence in a Mouse Model of Down Syndrome

Rusu

Kukreja

et al. 2023

eNeuro

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“…Furthermore, an intricate interplay exists between oxidative stress and proteostasis, as one of the early responses to excessive ROS is the induction of mitophagy, which can reduce oxidative damage and ROS production ( Shefa et al, 2019 ). Multiple lines of evidence have shown that ROS interacts with both ubiquitin-dependent and receptor-dependent mitophagy pathways ( De Gaetano et al, 2021 ; Puente-Bedia et al, 2022 ) ( Figure 2C ).…”

Section: Discussionmentioning

confidence: 99%

Temperature- and chemical-induced neurotoxicity in zebrafish

Toni,

Arena,

Cioni

et al. 2023

Front. Physiol.

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Throughout their lives, humans encounter a plethora of substances capable of inducing neurotoxic effects, including drugs, heavy metals and pesticides. Neurotoxicity manifests when exposure to these chemicals disrupts the normal functioning of the nervous system, and some neurotoxic agents have been linked to neurodegenerative pathologies such as Parkinson’s and Alzheimer’s disease. The growing concern surrounding the neurotoxic impacts of both naturally occurring and man-made toxic substances necessitates the identification of animal models for rapid testing across a wide spectrum of substances and concentrations, and the utilization of tools capable of detecting nervous system alterations spanning from the molecular level up to the behavioural one. Zebrafish (Danio rerio) is gaining prominence in the field of neuroscience due to its versatility. The possibility of analysing all developmental stages (embryo, larva and adult), applying the most common “omics” approaches (transcriptomics, proteomics, lipidomics, etc.) and conducting a wide range of behavioural tests makes zebrafish an excellent model for neurotoxicity studies. This review delves into the main experimental approaches adopted and the main markers analysed in neurotoxicity studies in zebrafish, showing that neurotoxic phenomena can be triggered not only by exposure to chemical substances but also by fluctuations in temperature. The findings presented here serve as a valuable resource for the study of neurotoxicity in zebrafish and define new scenarios in ecotoxicology suggesting that alterations in temperature can synergistically compound the neurotoxic effects of chemical substances, intensifying their detrimental impact on fish populations.

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“…Given reports of increased DNA damage and chronic neuroinflammation in DS and the Ts65Dn brain [63][64][65] , we hypothesized that subpopulations of Ts65Dn cells would exhibit accelerated senescence. Senescent cells accumulate in aged tissues due to exhaustion of proliferation-competent cells 66,67 .…”

Section: Cortical Ts65dn Opcs Exhibit Enrichment For a Senescence-ass...mentioning

confidence: 99%

Single-nucleus profiling identifies accelerated oligodendrocyte precursor cell senescence in a mouse model of Down Syndrome

Rusu

Kukreja

et al. 2023

Preprint

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Down Syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive disability. However, the mechanisms by which triplication of human chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus RNA- and ATAC-seq analysis of the cortex. We identify cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discover enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We find that senescence is restricted to a subset of cortical OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescues cortical OPC proliferation, restores microglial homeostasis, and improves contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS.

show abstract

Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome

Cited by 8 publications

References 140 publications

Single-Nucleus Profiling Identifies Accelerated Oligodendrocyte Precursor Cell Senescence in a Mouse Model of Down Syndrome

Single-Nucleus Profiling Identifies Accelerated Oligodendrocyte Precursor Cell Senescence in a Mouse Model of Down Syndrome

Temperature- and chemical-induced neurotoxicity in zebrafish

Single-nucleus profiling identifies accelerated oligodendrocyte precursor cell senescence in a mouse model of Down Syndrome

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