Activation of endogenous retroviruses during brain development causes an inflammatory response

Jönsson, Marie E.; Garza, Raquel; Sharma, Yogita; Petri, Rebecca; Södersten, Erik; Johansson, Jenny; Johansson, Peter; Atacho, Diahann A. M.; Pircs, Karolina; Madsen, Sofia; Yudovich, David; Ramakrishnan, Ramprasad; Holmberg, Johan; Larsson, Jonas; Jern, Patric; Jakobsson, Johan

doi:10.15252/embj.2020106423

Cited by 41 publications

(40 citation statements)

References 91 publications

(179 reference statements)

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“…Finally, the production and aggregation of proteins encoded by ERVs activated during development were found to be another source of neuroinflammation appearing in the adult age. More importantly, this study showed for the first time that TEs expression alone in the absence of other alterations or pathology can be sufficient to induce microglial activation, a characteristic feature seen in most NDs [209]. Further studies are needed to examine whether and to what extent reawakening of TEs and LINE‐1 activity contribute to neuroinflammation in NDs.…”

Section: Tes As Potential Pathogenic Driversmentioning

confidence: 95%

Transposable elements as new players in neurodegenerative diseases

et al. 2021

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Neurodegenerative diseases (NDs), including the most prevalent Alzheimer’s disease and Parkinson disease, share common pathological features. Despite decades of gene‐centric approaches, the molecular mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered ‘junk’ DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP‐43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.

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Section: Tes As Potential Pathogenic Driversmentioning

confidence: 95%

Transposable elements as new players in neurodegenerative diseases

et al. 2021

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“…Furthermore, KAP1-mediated silencing is especially important for brain development. Its depletion in neural progenitor cells aberrantly activates ERV expression while having no impact on adult neural cells [ 63 ].…”

Section: Epigenetic Control Of Hervsmentioning

confidence: 99%

Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease

Giménez-Orenga

Oltra

2021

Pharmaceuticals

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Human endogenous retroviruses (HERVs) are ancient retroviral DNA sequences established into germline. They contain regulatory elements and encoded proteins few of which may provide benefits to hosts when co-opted as cellular genes. Their tight regulation is mainly achieved by epigenetic mechanisms, which can be altered by environmental factors, e.g., viral infections, leading to HERV activation. The aberrant expression of HERVs associates with neurological diseases, such as multiple sclerosis (MS) or amyotrophic lateral sclerosis (ALS), inflammatory processes and neurodegeneration. This review summarizes the recent advances on the epigenetic mechanisms controlling HERV expression and the pathogenic effects triggered by HERV de-repression. This article ends by describing new, promising therapies, targeting HERV elements, one of which, temelimab, has completed phase II trials with encouraging results in treating MS. The information gathered here may turn helpful in the design of new strategies to unveil epigenetic failures behind HERV-triggered diseases, opening new possibilities for druggable targets and/or for extending the use of temelimab to treat other associated diseases.

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“…CRISPR/Cas9‐based deletion of KAP1 (TRIM28), an epigenetic co-repressor protein, results in upregulation of ERVs in mouse NPCs in vitro ( Jönsson et al, 2021 ). However, there is no activation of ERVs in adult neurons, in case a vector targeting KAP1 (TRIM28) is injected into the forebrain of adult Cas9‐GFP mice ( Lee et al, 2020b ).…”

Section: Regulatory Factors For Hervsmentioning

confidence: 99%

Human Endogenous Retroviruses as Gene Expression Regulators: Insights from Animal Models into Human Diseases

Durnaoglu

Lee

Ahnn

2021

Molecules and Cells

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The human genome contains many retroviral elements called human endogenous retroviruses (HERVs), resulting from the integration of retroviruses throughout evolution. HERVs once were considered inactive junk because they are not replication-competent, primarily localized in the heterochromatin, and silenced by methylation. But HERVs are now clearly shown to actively regulate gene expression in various physiological and pathological conditions such as developmental processes, immune regulation, cancers, autoimmune diseases, and neurological disorders. Recent studies report that HERVs are activated in patients suffering from coronavirus disease 2019 (COVID-19), the current pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. In this review, we describe internal and external factors that influence HERV activities. We also present evidence showing the gene regulatory activity of HERV LTRs (long terminal repeats) in model organisms such as mice, rats, zebrafish, and invertebrate models of worms and flies. Finally, we discuss several molecular and cellular pathways involving various transcription factors and receptors, through which HERVs affect downstream cellular and physiological events such as epigenetic modifications, calcium influx, protein phosphorylation, and cytokine release. Understanding how HERVs participate in various physiological and pathological processes will help develop a strategy to generate effective therapeutic approaches targeting HERVs.

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Activation of endogenous retroviruses during brain development causes an inflammatory response

Cited by 41 publications

References 91 publications

Transposable elements as new players in neurodegenerative diseases

Transposable elements as new players in neurodegenerative diseases

Human Endogenous Retrovirus as Therapeutic Targets in Neurologic Disease

Human Endogenous Retroviruses as Gene Expression Regulators: Insights from Animal Models into Human Diseases

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