8 research outputs found
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Transposable Elements, Inflammation, and Neurological Disease.
Transposable Elements (TE) are mobile DNA elements that can replicate and insert themselves into different locations within the host genome. Their propensity to self-propagate has a myriad of consequences and yet their biological significance is not well-understood. Indeed, retrotransposons have evaded evolutionary attempts at repression and may contribute to somatic mosaicism. Retrotransposons are emerging as potent regulatory elements within the human genome. In the diseased state, there is mounting evidence that endogenous retroelements play a role in etiopathogenesis of inflammatory diseases, with a disposition for both autoimmune and neurological disorders. We postulate that active mobile genetic elements contribute more to human disease pathogenesis than previously thought
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Modeling MeCP2 loss-of-function in human iPSC-derived astrocytes highlights LINE-1 retrotransposon as contributor to neuroinflammation
Long interspersed nuclear element-1 (LINE-1) are endogenous, self-propagating genomic sequences that comprise ~17% of the human genome. Retrotransposons play a critical role in genomic and cellular instability, particularly in various forms of human disease. In the diseased state, there is mounting evidence that endogenous retroelements play a role in etiopathogenesis of inflammatory diseases. Mutations in methyl-CpG- binding protein 2 (MeCP2), widely regarded as a global methylator and transcriptional repressor, result in increased LINE-1 expression and activity. Patients with mutations in MeCP2 have subclinical inflammatory phenotypes and cytokine dysregulation. Although de novo LINE-1 activity seems to occur frequently in neurons, little is known about the contribution of this element in glial cells. Astrocytes with mutations in MECP2 are abnormal in several key functions, thus we sought to investigate astrocyte-mediated inflammation caused by MeCP2 loss-of-function mutations. We generated iPSC-derived astrocytes from MeCP2-KO and healthy controls to observe whether LINE-1, which we know to be upregulated, contributes to the inflammatory phenotype observed. We chronically treated our cells with reverse transcriptase inhibitors (RTi) to reduce endogenous LINE-1 activity. Interestingly, we found upregulation of neuroinflammatory- related genes, increased levels of the proinflammatory cytokine IL-6 as well as an increase in reactive oxygen species, extracellular glutamate and glutathione levels in MeCP2-mutant astrocyte cultures when compared to control cells. Remarkably, inhibition of LINE-1 with RTis improved most of these pathological phenotypes in mutated cells. We hope our work brings further attention to mobile genetic elements, as they contribute more to disease pathologies than previously thought
Recommended from our members
Modeling MeCP2 loss-of-function in human iPSC-derived astrocytes highlights LINE-1 retrotransposon as contributor to neuroinflammation
Long interspersed nuclear element-1 (LINE-1) are endogenous, self-propagating genomic sequences that comprise ~17% of the human genome. Retrotransposons play a critical role in genomic and cellular instability, particularly in various forms of human disease. In the diseased state, there is mounting evidence that endogenous retroelements play a role in etiopathogenesis of inflammatory diseases. Mutations in methyl-CpG- binding protein 2 (MeCP2), widely regarded as a global methylator and transcriptional repressor, result in increased LINE-1 expression and activity. Patients with mutations in MeCP2 have subclinical inflammatory phenotypes and cytokine dysregulation. Although de novo LINE-1 activity seems to occur frequently in neurons, little is known about the contribution of this element in glial cells. Astrocytes with mutations in MECP2 are abnormal in several key functions, thus we sought to investigate astrocyte-mediated inflammation caused by MeCP2 loss-of-function mutations. We generated iPSC-derived astrocytes from MeCP2-KO and healthy controls to observe whether LINE-1, which we know to be upregulated, contributes to the inflammatory phenotype observed. We chronically treated our cells with reverse transcriptase inhibitors (RTi) to reduce endogenous LINE-1 activity. Interestingly, we found upregulation of neuroinflammatory- related genes, increased levels of the proinflammatory cytokine IL-6 as well as an increase in reactive oxygen species, extracellular glutamate and glutathione levels in MeCP2-mutant astrocyte cultures when compared to control cells. Remarkably, inhibition of LINE-1 with RTis improved most of these pathological phenotypes in mutated cells. We hope our work brings further attention to mobile genetic elements, as they contribute more to disease pathologies than previously thought
Recommended from our members
Transposable Elements, Inflammation, and Neurological Disease.
Transposable Elements (TE) are mobile DNA elements that can replicate and insert themselves into different locations within the host genome. Their propensity to self-propagate has a myriad of consequences and yet their biological significance is not well-understood. Indeed, retrotransposons have evaded evolutionary attempts at repression and may contribute to somatic mosaicism. Retrotransposons are emerging as potent regulatory elements within the human genome. In the diseased state, there is mounting evidence that endogenous retroelements play a role in etiopathogenesis of inflammatory diseases, with a disposition for both autoimmune and neurological disorders. We postulate that active mobile genetic elements contribute more to human disease pathogenesis than previously thought
SARS-CoV-2 infects human brain organoids causing cell death and loss of synapses that can be rescued by treatment with Sofosbuvir.
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which was rapidly declared a pandemic by the World Health Organization (WHO). Early clinical symptomatology focused mainly on respiratory illnesses. However, a variety of neurological manifestations in both adults and newborns are now well-documented. To experimentally determine whether SARS-CoV-2 could replicate in and affect human brain cells, we infected iPSC-derived human brain organoids. Here, we show that SARS-CoV-2 can productively replicate and promote death of neural cells, including cortical neurons. This phenotype was accompanied by loss of excitatory synapses in neurons. Notably, we found that the U.S. Food and Drug Administration (FDA)-approved antiviral Sofosbuvir was able to inhibit SARS-CoV-2 replication and rescued these neuronal alterations in infected brain organoids. Given the urgent need for readily available antivirals, these results provide a cellular basis supporting repurposed antivirals as a strategic treatment to alleviate neurocytological defects that may underlie COVID-19- related neurological symptoms