The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis

Dolei, Antonina

doi:10.1177/1352458517737370

Cited by 47 publications

(49 citation statements)

References 35 publications

(121 reference statements)

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“…We focused on HERV-K because, of the dozens of HERV families, only HERV-W and HERV-K were repeatedly reported to have potentially pathogenic properties, both linked to the proteins coded by their env genes. The HERV-W is linked to multiple sclerosis [ 49 , 50 ], and the HERV-K to cancer [ 5 , 51 ] and amyotrophic lateral sclerosis [ 52 , 53 , 54 ].…”

Section: Discussionmentioning

confidence: 99%

Disruption by SaCas9 Endonuclease of HERV-Kenv, a Retroviral Gene with Oncogenic and Neuropathogenic Potential, Inhibits Molecules Involved in Cancer and Amyotrophic Lateral Sclerosis

Ibba

Piu

Uleri

et al. 2018

Viruses

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The human endogenous retrovirus (HERV)-K, human mouse mammary tumor virus like-2 (HML-2) subgroup of HERVs is activated in several tumors and has been related to prostate cancer progression and motor neuron diseases. The cellular splicing factor 2/alternative splicing factor (SF2/ASF) is a positive regulator of gene expression, coded by a potent proto-oncogene, amplified, and abnormally expressed in tumors. TAR DNA-binding protein-43 (TDP-43) is a DNA/RNA-binding protein, negative regulator of alternative splicing, known for causing neurodegeneration, and with complex roles in oncogenesis. We used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, with the Cas9 system from Staphylococcus aureus (SaCas9), to disrupt the HERV-K(HML-2)env gene, and evaluated the effects on cultured cells. The tool was tested on human prostate cancer LNCaP cells, whose HERV-Kenv transcription profile is known. It caused HERV-K(HML-2)env disruption (the first reported of a HERV gene), as evaluated by DNA sequencing, and inhibition of env transcripts and proteins. The HERV-K(HML-2)env disruption was found to interfere with important regulators of cell expression and proliferation, involved in manaling, RNA-binding, and alternative splicing, such as epidermal growth factor receptor (EGF-R), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), SF2/ASF, and TDP-43. These novel findings suggest that HERV-K is not an innocent bystander, they reinforce its links to oncogenesis and motor neuron diseases, and they open potential innovative therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Disruption by SaCas9 Endonuclease of HERV-Kenv, a Retroviral Gene with Oncogenic and Neuropathogenic Potential, Inhibits Molecules Involved in Cancer and Amyotrophic Lateral Sclerosis

Ibba

Piu

Uleri

et al. 2018

Viruses

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“…Yet there is mounting evidence that MS is tightly linked to EBV infection, whereby viral expression was observed in the CNS of MS cases 27 , 28 . It is also of importance to note that EBV is capable to express latent endogenous retroviral genes in the human genome, some of which are pro-inflammatory and have super-antigenic properties and have been shown to cause neurotoxic effects 29 . It is not possible to state whether EBV infection is the sole contributor or initiator of observed MS-based molecular changes in blood based on our analysis, but the literature suggests that multiple health-affecting causes are contributing factors to MS pathophysiology and/or initiation events, of which EBV is one of them.…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of Multiple Sclerosis using a systems biology approach

Cervantes-Gracia

Husi

2018

Sci Rep

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Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory-demyelinating events in the central nervous system. Despite more than 40 years of MS research its aetiology remains unknown. This study aims to identify the most frequently reported and consistently regulated molecules in MS in order to generate molecular interaction networks and thereby leading to the identification of deregulated processes and pathways which could give an insight of the underlying molecular mechanisms of MS. Driven by an integrative systems biology approach, gene-expression profiling datasets were combined and stratified into “Non-treated” and “Treated” groups and additionally compared to other disease patterns. Molecular identifiers from dataset comparisons were matched to our Multiple Sclerosis database (MuScle; www.padb.org/muscle). From 5079 statistically significant molecules, correlation analysis within groups identified a panel of 16 high-confidence genes unique to the naïve MS phenotype, whereas the “Treated” group reflected a common pattern associated with autoimmune disease. Pathway and gene-ontology clustering identified the Interferon gamma signalling pathway as the most relevant amongst all significant molecules, and viral infections as the most likely cause of all down-stream events observed. This hypothesis-free approach revealed the most significant molecular events amongst different MS phenotypes which can be used for further detailed studies.

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“…Soluble CD163 (sCD163) measured in serum has been examined as a biomarker in MS [79], while their study also confirmed the presence of human endogenous retrovirus (HERV-W) envelope epitopes on non-classical monocytes from patients with MS. It has previously been suggested that viral infections such as Epstein-Barr and subsequent activation of HERV-W, also known as the MS-associated retroviral element (MSRV), may be involved in the inflammatory demise of oligodendrocytes [80].…”

Section: Discussionmentioning

confidence: 99%

Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing

Rensburg

Peeters

Toorn

et al. 2019

Molecular Genetics and Metabolism Reports

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BackgroundMultiple sclerosis is a disorder related to demyelination of axons. Iron is an essential cofactor in myelin synthesis. Previously, we described two children (males of mixed ancestry) with relapsing-remitting multiple sclerosis (RRMS) where long-term remission was achieved by regular iron supplementation. A genetic defect in iron metabolism was postulated, suggesting that more advanced genetic studies could shed new light on disease pathophysiology related to iron.MethodsWhole exome sequencing (WES) was performed to identify causal pathways. Blood tests were performed over a 10 year period to monitor the long-term effect of a supplementation regimen. Clinical wellbeing was assessed quarterly by a pediatric neurologist and regular feedback was obtained from the schoolteachers.ResultsWES revealed gene variants involved in iron absorption and transport, in the transmembrane protease, serine 6 (TMPRSS6) and transferrin (TF) genes; multiple genetic variants in CUBN, which encodes cubilin (a receptor involved in the absorption of vitamin B12 as well as the reabsorption of transferrin-bound iron and vitamin D in the kidneys); SLC25A37 (involved in iron transport into mitochondria) and CD163 (a scavenger receptor involved in hemorrhage resolution). Variants were also found in COQ3, involved with synthesis of Coenzyme Q10 in mitochondria. Neither of the children had the HLA-DRB1*1501 allele associated with increased genetic risk for MS, suggesting that the genetic contribution of iron-related genetic variants may be instrumental in childhood MS. In both children the RRMS has remained stable without activity over the last 10 years since initiation of nutritional supplementation and maintenance of normal iron levels, confirming the role of iron deficiency in disease pathogenesis in these patients.ConclusionOur findings highlight the potential value of WES to identify heritable risk factors that could affect the reabsorption of transferrin-bound iron in the kidneys causing sustained iron loss, together with inhibition of vitamin B12 absorption and vitamin D reabsorption (CUBN) and iron transport into mitochondria (SLC25A37) as the sole site of heme synthesis. This supports a model for RRMS in children with an apparent iron-deficient biochemical subtype of MS, with oligodendrocyte cell death and impaired myelination possibly caused by deficits of energy- and antioxidant capacity in mitochondria.

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The aliens inside us: HERV-W endogenous retroviruses and multiple sclerosis

Cited by 47 publications

References 35 publications

Disruption by SaCas9 Endonuclease of HERV-Kenv, a Retroviral Gene with Oncogenic and Neuropathogenic Potential, Inhibits Molecules Involved in Cancer and Amyotrophic Lateral Sclerosis

Disruption by SaCas9 Endonuclease of HERV-Kenv, a Retroviral Gene with Oncogenic and Neuropathogenic Potential, Inhibits Molecules Involved in Cancer and Amyotrophic Lateral Sclerosis

Integrative analysis of Multiple Sclerosis using a systems biology approach

Identification of an iron-responsive subtype in two children diagnosed with relapsing-remitting multiple sclerosis using whole exome sequencing

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